Irreversible inhibitors of menin-mll interaction

ABSTRACT

Disclosed herein are heterocyclic compounds that inhibit the binding of menin and MLL or MLL fusion proteins. Also described are specific irreversible inhibitors of menin-MLL interaction. Also disclosed are pharmaceutical compositions that include the compounds. Methods of using the menin-MLL irreversible inhibitors are disclosed, alone or in combination with other therapeutic agents, for the treatment of autoimmune diseases or conditions, heteroimmune diseases or conditions, cancer, including lymphoma, leukemia and other diseases or conditions dependent on menin-MLL interaction.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a divisional application of U.S. application Ser.No. 17/352,146, filed Jun. 18, 2021, which is a continuation of U.S.application Ser. No. 16/732,226, filed Dec. 31, 2019, now U.S. Pat. No.11,084,825, issued Aug. 10, 2021, which claims priority to, and thebenefit of U.S. Provisional Application No. 62/786,842, filed Dec. 31,2018, the entire contents of each of which are herein incorporated byreference in their entirety for all purposes.

FIELD OF THE INVENTION

Described herein are compounds, methods of making such compounds,pharmaceutical compositions and medicaments containing such compounds,and methods of using such compounds and compositions to inhibit theactivity of menin-MLL. (And may also serve as an anti-tumor agentthrough off-target activity by impacting other protein-proteininteractions as well as kinases.)

BACKGROUND OF THE INVENTION

The Histone-lysine N-methyltransferase 2 (KMT2) family of proteins,which currently consists of at least 5 members, methylate lysine 4 onthe histone H3 tails at important regulatory regions in the genome andthereby impart crucial functions through the modulation of chromatinstructures and DNA accessibility (Morera, Lübbert, and Jung, Clin.Epigenetics 8, 57-(2016)). These enzymes are known to play an importantrole in the regulation of gene expression during early development andhematopoiesis (Rao & Dou., Nat. Rev. Cancer 15, 334-346 (2015)).

The human KMT2 family was initially named the mixed-lineage leukaemia(MLL) family, owing to the role of the first-found member in thisdisease, KMT2A which is still commonly referred to as MLL1 or MLL inroutine clinical practice.

KMT2A (MLL1) is frequently found to be cytogenetically targeted inseveral types of leukemia (e.g. ALL and AML), and in those cases wherebalanced chromosomal translocations are found, these typically targetKMT2A (MLL1) and one of over 80 translocation partner genes that havebeen described to date (Winters and Bernt, Front. Pediatr. 5, 4 (2017)).These chromosomal anomalies often result in the formation of fusiongenes that encode fusion proteins which are believed to be causallyrelated to the onset and/or progression of the disease. Inhibition ofmenin may be a promising strategy for treating MLL related diseases,including leukemia.

M-525 is a highly potent, irreversible small molecule inhibitor of themenin-MLL protein-protein interaction. It forms a covalent bond withCys329 residue in menin. M-525 demonstrate high cellular specificityover non-MLL leukemia cells and is >30 times more potent that thecorresponding reversible inhibitors. See S. Xu et al. Angewandte ChemieInternational Ed. 57(6), 1601-1605 (2017).

SUMMARY OF THE INVENTION

Described herein are irreversible inhibitors of menin-MLL interaction.Also described herein are specific heterocyclic irreversible inhibitorsof menin-MLL or MLL fusion proteins interaction.

Also described herein are methods for synthesizing such irreversibleinhibitors, methods for using such irreversible inhibitors in thetreatment of diseases (including diseases wherein inhibition ofmenin-MLL interaction provides therapeutic benefit to a patient havingthe disease). Further described are pharmaceutical compositions thatinclude an inhibitor of menin-MLL interaction. Specifically, describedherein are compounds and methods of use thereof to inhibit interactionof menin with MLL oncoproteins (e.g., MLL1, MLL2, MLL-fusiononcoproteins).

Specifically described herein are irreversible inhibitors of menin-MLLinteraction that form a covalent bond with a cysteine residue on menin.Further described herein are irreversible inhibitors of menin-MLLinteraction that form a covalent bond with a Cys329 residue on menin.Also described are pharmaceutical formulations that include anirreversible inhibitor of menin.

Thus, in some embodiments, the present invention provides methods forpreventing, treating or ameliorating in a mammal a disease or conditionthat is causally related to the aberrant activity of a menin-MLLinteraction in vivo, which comprises administering to the mammal aneffective disease-treating or condition-treating amount of a compoundaccording to Formula (I) having the structure:

or a pharmaceutically acceptable salt thereof,wherein:

A is C or N;

Cy is substituted or unsubstituted

Q is N, —N(H)—, —O—, or —S—; Z is —CR^(5a)═ or —N═;

X is —NR^(3a)—, —C(R^(3b))₂—, or —O—;Y is a single bond, —NR^(3a)—, —C(R^(3b))₂—, or —O—;

W is —C(O)—, —S(O)—, or —S(O)₂—;

one of R¹ and R² is Cy²-N(H)C(O)—C(R^(6a))═C(R^(6b))(R^(6c)), orCH₂—Cy²-N(H)C(O)—C(R^(6a))═C(R^(6b))(R^(6c)); and other is H, C₁₋₆alkyl, C₁₋₆ haloalkyl, halo, or CN;

Cy² is an optionally substituted group selected from phenyl, pyridyl, ora 4-7 membered heterocycloalkyl ring having 1-2 heteroatomsindependently selected from nitrogen, oxygen, or sulfur;

each R^(3a), and R^(3b) is independently H or C₁₋₆ alkyl;each R^(4a) and R^(4b) is independently H, halo, CN, OR, —N(R)₂,—C(O)N(R)₂, —NRC(O)R, —SO₂R, —C(O)R, —CO₂R, or an optionally substitutedgroup selected from C₁₋₆ alkyl, C₃₋₇ cycloalkyl, a 4-7 memberedheterocycloalkyl ring having 1-2 heteroatoms independently selected fromnitrogen, oxygen, or sulfur, phenyl, an 8-10 membered bicyclic arylring, and a 5-6 membered heteroaryl ring having 1-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur;each R is independently H, or an optionally substituted group selectedfrom C₁₋₆ aliphatic, phenyl, an 8-10 membered bicyclic aryl ring, a 4-7membered saturated or partially unsaturated heterocyclic ring having 1-2heteroatoms independently selected from nitrogen, oxygen, or sulfur, anda 5-6 membered heteroaryl ring having 1-4 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur, or:two R groups on the same nitrogen are taken together with theirintervening atoms to form a 4-7 membered saturated, partiallyunsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition tothe nitrogen, independently selected from nitrogen, oxygen, or sulfur;R^(5a) is H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, halo, or CN;each R^(6a) and R^(6b) is independently H or C₁₋₆ alkyl; or R^(6a) andR^(6b) are joined together to form a bond;R^(6c) is H or substituted or unsubstituted C₁₋₆ alkyl;m is 1, 2, or 3; and n is 1, 2, 3, or 4.

In some embodiments, the present invention provides a compound accordingto Formula (I) having the structure:

or a pharmaceutically acceptable salt thereof,wherein:

A is C or N;

Cy is substituted or unsubstituted

Q is N, —N(H)—, —O—, or —S—; Z is —CR^(5a)═ or —N═;

X is —NR^(3a)—, —C(R^(3b))₂—, or —O—;Y is a single bond, —NR^(3a)—, —C(R^(3b))₂—, or —O—;

W is —C(O)—, —S(O)—, or —S(O)₂—;

one of R¹ and R² is Cy²-N(H)C(O)—C(R^(6a))═C(R^(6b))(R^(6c)), orCH₂—Cy²-N(H)C(O)—C(R^(6a))═C(R^(6b))(R^(6c)); and other is H, C₁₋₆alkyl, C₁₋₆ haloalkyl, halo, or CN;Cy² is an optionally substituted group selected from phenyl, pyridyl, ora 4-7 membered heterocycloalkyl ring having 1-2 heteroatomsindependently selected from nitrogen, oxygen, or sulfur;each R^(3a), and R^(3b) is independently H or C₁₋₆ alkyl;each R^(4a) and R^(4b) is independently H, halo, CN, OR, —N(R)₂,—C(O)N(R)₂, —NRC(O)R, —SO₂R, —C(O)R, —CO₂R, or an optionally substitutedgroup selected from C₁₋₆ alkyl, C₃₋₇ cycloalkyl, a 4-7 memberedheterocycloalkyl ring having 1-2 heteroatoms independently selected fromnitrogen, oxygen, or sulfur, phenyl, an 8-10 membered bicyclic arylring, and a 5-6 membered heteroaryl ring having 1-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur;each R is independently H, or an optionally substituted group selectedfrom C₁₋₆ aliphatic, phenyl, an 8-10 membered bicyclic aryl ring, a 4-7membered saturated or partially unsaturated heterocyclic ring having 1-2heteroatoms independently selected from nitrogen, oxygen, or sulfur, anda 5-6 membered heteroaryl ring having 1-4 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur, or:two R groups on the same nitrogen are taken together with theirintervening atoms to form a 4-7 membered saturated, partiallyunsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition tothe nitrogen, independently selected from nitrogen, oxygen, or sulfur;R^(5a) is H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, halo, or CN;each R^(6a) and R^(6b) is independently H or C₁₋₆ alkyl; or R^(6a) andR^(6b) are joined together to form a bond;R^(6c) is H or substituted or unsubstituted C₁₋₆ alkyl;m is 1, 2, or 3; and n is 1, 2, 3, or 4.

In some embodiments, the present invention provides a compound accordingto Formula (XXI):

or a pharmaceutically acceptable salt thereof,wherein A, Cy, Cy², R^(4b), R^(6a), R^(6b), R^(6c), m, and n are asdescribed for formula (I); and each R⁸ and R⁹ is independently H, C₁₋₆alkyl, C₁₋₆ haloalkyl, halo, or CN.

In some embodiments, X is —N(H)— and Y is —NH—, —C(H)₂— or O. In someembodiments, each of X and Y is —N(H)—.

In some embodiments, W is —S(O)—, or —S(O)₂—. In a particularembodiment, W is —C(O)—.

In some embodiments, —X—W—Y— is —N(H)—C(O)—N(H)—, —N(H)—C(O)—CH₂—,—CH₂—C(O)—N(H)—, —N(H)—S(O)—N(H)—, —N(H)—S(O)—CH₂—, —CH₂—S(O)—N(H)—,—N(H)—S(O)₂—N(H)—, —N(H)—S(O)₂—CH₂—, —CH₂—S(O)₂—N(H)—, or —N(H)—C(O)—.

In some embodiments, the compound is according to formula (IIa), (IIb),(IIc) or (IId):

or a pharmaceutically acceptable salt thereof.

In some embodiments, R² is H, Me, Et, i-Pr, CF₃, F, Cl, OMe, OEt, or CN.

In some embodiments, the compound is according to formula (XV):

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is according to formula (XVI):

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is according to formula XVII

or a pharmaceutically acceptable salt thereof.

In some embodiments, the active site is a cavity in which the compoundor the moiety binds to the MLL site on the menin. In some embodiments,the active site is MEN1 at the MLL binding site.

In some embodiments, the disease or condition is an autoimmune disease,a heteroimmune disease, a cancer, mastocytosis, osteoporosis or boneresorption disorder, or an inflammatory disease.

In some embodiments, the compounds of the invention may also serve as ananti-tumor agents through off-target activity by impacting otherprotein-protein interactions as well as kinases.

In some embodiments, the present invention provides pharmaceuticalcompositions comprising a therapeutically effective amount of a compoundof Formula (I) and a pharmaceutically acceptable excipient. In someembodiments, the pharmaceutical composition comprising the compound ofFormula (I) is formulated for a route of administration selected fromoral administration, parenteral administration, buccal administration,nasal administration, topical administration, or rectal administration.In some embodiments, the present invention provides methods for treatingan autoimmune disease or condition comprising administering to a patientin need a therapeutically effective amount of a compound of Formula (I).In some embodiments the autoimmune disease is selected from rheumatoidarthritis or lupus. In some embodiments, the present invention providesa method for treating a heteroimmune disease or condition comprisingadministering to a patient in need a therapeutically effective amount ofa compound of Formula (I). In some embodiments the present inventionprovides a method for treating a cancer comprising administering to apatient in need a therapeutically effective amount of a compound ofFormula (I). In some embodiments, the cancer is a myeloid line of bloodcells.

In some embodiments, the cancer is a lymphoid line of blood cell. Insome embodiments, the cancer is a B-cell proliferative disorder. In someembodiments, the cancer is a lymphoid line of blood cells.

In some embodiments the myeloid line of blood cells is acute myeloidleukemia. In some embodiments the lymphoid line of blood cells is acutelymphoblastic leukemia. In some embodiments the B-cell proliferativedisorder is diffuse large B cell lymphoma, follicular lymphoma orchronic lymphocytic leukemia. In some embodiments the cancer (softtissue) is glioblastoma and pancreatic cancer. In some embodiments thecancer is renal cell carcinoma.

In some embodiments, the present invention provides a method fortreating mastocytosis comprising administering to a patient in need atherapeutically effective amount of a compound of Formula (I).

In some embodiments, the present invention provides a method fortreating osteoporosis or bone resorption disorders comprisingadministering to a patient in need a therapeutically effective amount ofa compound of Formula (I).

In some embodiments, the present invention provides a method fortreating an inflammatory disease or condition comprising administeringto a patient in need a therapeutically effective amount of a compound ofFormula (I).

Any combination of the groups described above for the various variablesis contemplated herein. It is understood that substituents andsubstitution patterns on the compounds provided herein can be selectedby one of ordinary skill in the art to provide compounds that arechemically stable and that can be synthesized by techniques known in theart, as well as those set forth herein.

In some embodiments, the present invention provides pharmaceuticalcompositions, which include a therapeutically effective amount of atleast one of any of the compounds herein, or a pharmaceuticallyacceptable salt, pharmaceutically active metabolite, pharmaceuticallyacceptable prodrug, or pharmaceutically acceptable solvate. In certainembodiments, compositions provided herein further include apharmaceutically acceptable diluent, excipient and/or binder.

Pharmaceutical compositions formulated for administration by anappropriate route and means containing effective concentrations of oneor more of the compounds provided herein, or pharmaceutically effectivederivatives thereof, that deliver amounts effective for the treatment,prevention, or amelioration of one or more symptoms of diseases,disorders or conditions that are modulated or otherwise affected byMenin-MLL activity, or in which Menin-MLL activity is implicated, areprovided. The effective amounts and concentrations are effective forameliorating any of the symptoms of any of the diseases, disorders orconditions disclosed herein.

In certain embodiments, provided herein is a pharmaceutical compositioncontaining: i) a physiologically acceptable carrier, diluent, and/orexcipient; and ii) one or more compounds provided herein.

In some embodiments, provided herein are methods for treating a patientby administering a compound provided herein. In some embodiments,provided herein is a method of inhibiting the activity of Menin-MLL, orof treating a disease, disorder, or condition, which would benefit frominhibition of Menin-MLL activity, in a patient, which includesadministering to the patient a therapeutically effective amount of atleast one of any of the compounds herein, or pharmaceutically acceptablesalt, pharmaceutically active metabolite, pharmaceutically acceptableprodrug, or pharmaceutically acceptable solvate.

In some embodiments, provided herein is the use of a compound disclosedherein for inhibiting Menin-MLL activity or for the treatment of adisease, disorder, or condition, which would benefit from inhibition ofMenin-MLL activity.

In some embodiments, compounds provided herein are administered to ahuman.

In some embodiments, compounds provided herein are orally administered.

In some embodiments, compounds provided herein are used for theformulation of a medicament for the inhibition of Menin-MLL activity. Insome embodiments, compounds provided herein are used for the formulationof a medicament for the inhibition of Menin-MLL activity.

Articles of manufacture including packaging material, a compound orcomposition or pharmaceutically acceptable derivative thereof providedherein, which is effective for inhibiting the activity of Menin-MLL,within the packaging material, and a label that indicates that thecompound or composition, or pharmaceutically acceptable salt,pharmaceutically active metabolite, pharmaceutically acceptable prodrug,or pharmaceutically acceptable solvate thereof, is used for inhibitingthe activity of Menin-MLL, are provided.

In some embodiments, provided herein is a method for inhibitingMenin-MLL activity in a subject in need thereof by administering to thesubject thereof a composition containing a therapeutically effectiveamount of at least one compound having the structure of Formula (I). Insome embodiments, the subject in need is suffering from an autoimmunedisease, e.g., inflammatory bowel disease, arthritis, lupus, rheumatoidarthritis, psoriatic arthritis, osteoarthritis, Still's disease,juvenile arthritis, diabetes, myasthenia gravis, Hashimoto'sthyroiditis, Ord's thyroiditis, Graves' disease Sjögren's syndrome,multiple sclerosis, Guillain-Barre syndrome, acute disseminatedencephalomyelitis, Addison's disease, opsoclonus-myoclonus syndrome,ankylosing spondylitis, antiphospholipid antibody syndrome, aplasticanemia, autoimmune hepatitis, coeliac disease, Goodpasture's syndrome,idiopathic thrombocytopenic purpura, optic neuritis, scleroderma,primary biliary cirrhosis, Reiter's syndrome, Takayasu's arteritis,temporal arteritis, warm autoimmune hemolytic anemia, Wegener'sgranulomatosis, psoriasis, alopecia universalis, Behçet's disease,chronic fatigue, dysautonomia, endometriosis, interstitial cystitis,neuromyotonia, scleroderma, or vulvodynia.

In some embodiments, the subject in need is suffering from aheteroimmune condition or disease, e.g., graft versus host disease,transplantation, transfusion, anaphylaxis, allergy, type Ihypersensitivity, allergic conjunctivitis, allergic rhinitis, or atopicdermatitis.

In certain embodiments, the subject in need is suffering from aninflammatory disease, e.g., asthma, appendicitis, blepharitis,bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis,cholecystitis, colitis, conjunctivitis, cystitis, dacryoadenitis,dermatitis, dermatomyositis, encephalitis, endocarditis, endometritis,enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis,fibrositis, gastritis, gastroenteritis, hepatitis, hidradenitissuppurativa, laryngitis, mastitis, meningitis, myelitis myocarditis,myositis, nephritis, oophoritis, orchitis, osteitis, otitis,pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis,pleuritis, phlebitis, pneumonitis, pneumonia, proctitis, prostatitis,pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis,tendonitis, tonsillitis, uveitis, vaginitis, vasculitis, or vulvitis.

In some embodiments, the subject in need is suffering from a cancer. Insome embodiments, the cancer is a B-cell proliferative disorder, e.g.,diffuse large B cell lymphoma, follicular lymphoma, chronic lymphocyticlymphoma, chronic lymphocytic leukemia, B-cell prolymphocytic leukemia,lymphoplasmacytic lymphoma/Waldenström macroglobulinemia, splenicmarginal zone lymphoma, plasma cell myeloma, plasmacytoma, extranodalmarginal zone B cell lymphoma, nodal marginal zone B cell lymphoma,mantle cell lymphoma, mediastinal (thymic) large B cell lymphoma,intravascular large B cell lymphoma, primary effusion lymphoma, burkittlymphoma/leukemia, or lymphomatoid granulomatosis. In some embodiments,where the subject is suffering from a cancer, an anti-cancer agent isadministered to the subject in addition to one of the above-mentionedcompounds.

In some embodiments, the subject in need is suffering from athromboembolic disorder, e.g., myocardial infarct, angina pectoris,reocclusion after angioplasty, restenosis after angioplasty, reocclusionafter aortocoronary bypass, restenosis after aortocoronary bypass,stroke, transitory ischemia, a peripheral arterial occlusive disorder,pulmonary embolism, or deep venous thrombosis.

In some embodiments, provided herein is a method for treating anautoimmune disease by administering to a subject in need thereof acomposition containing a therapeutically effective amount of at leastone compound having the structure of Formula (I)-(XVII). In someembodiments, the autoimmune disease is arthritis. In some embodiments,the autoimmune disease is lupus. In some embodiments, the autoimmunedisease is inflammatory bowel disease (including Crohn's disease andulcerative colitis), rheumatoid arthritis, psoriatic arthritis,osteoarthritis, Still's disease, juvenile arthritis, lupus, diabetes,myasthenia gravis, Hashimoto's thyroiditis, Ord's thyroiditis, Graves'disease Sjögren's syndrome, multiple sclerosis, Guillain-Barre syndrome,acute disseminated encephalomyelitis, Addison's disease,opsoclonus-myoclonus syndrome, ankylosing spondylitis, antiphospholipidantibody syndrome, aplastic anemia, autoimmune hepatitis, coeliacdisease, Goodpasture's syndrome, idiopathic thrombocytopenic purpura,optic neuritis, scleroderma, primary biliary cirrhosis, Reiter'ssyndrome, Takayasu's arteritis, temporal arteritis, warm autoimmunehemolytic anemia, Wegener's granulomatosis, psoriasis, alopeciauniversalis, Behçet's disease, chronic fatigue, dysautonomia,endometriosis, interstitial cystitis, neuromyotonia, scleroderma, orvulvodynia.

In some embodiments, provided herein is a method for treating aheteroimmune condition or disease by administering to a subject in needthereof a composition containing a therapeutically effective amount ofat least one compound having the structure Formula (I)-(XVII). In someembodiments, the heteroimmune condition or disease is graft versus hostdisease, transplantation, transfusion, anaphylaxis, allergy, type Ihypersensitivity, allergic conjunctivitis, allergic rhinitis, or atopicdermatitis.

In some embodiments, provided herein is a method for treating aninflammatory disease by administering to a subject in need thereof acomposition containing a therapeutically effective amount of at leastone compound having the structure of Formula (I)-(XVII). In someembodiments, the inflammatory disease is asthma, inflammatory boweldisease (including Crohn's disease and ulcerative colitis),appendicitis, blepharitis, bronchiolitis, bronchitis, bursitis,cervicitis, cholangitis, cholecystitis, colitis, conjunctivitis,cystitis, dacryoadenitis, dermatitis, dermatomyositis, encephalitis,endocarditis, endometritis, enteritis, enterocolitis, epicondylitis,epididymitis, fasciitis, fibrositis, gastritis, gastroenteritis,hepatitis, hidradenitis suppurativa, laryngitis, mastitis, meningitis,myelitis myocarditis, myositis, nephritis, oophoritis, orchitis,osteitis, otitis, pancreatitis, parotitis, pericarditis, peritonitis,pharyngitis, pleuritis, phlebitis, pneumonitis, pneumonia, proctitis,prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis,stomatitis, synovitis, tendonitis, tonsillitis, uveitis, vaginitis,vasculitis, or vulvitis.

In some embodiments, provided herein is a method for treating a cancerby administering to a subject in need thereof a composition containing atherapeutically effective amount of at least one compound having thestructure of Formula (I)-(XVII). In some embodiments, the cancer is aB-cell proliferative disorder, e.g., diffuse large B cell lymphoma,follicular lymphoma, chronic lymphocytic lymphoma, chronic lymphocyticleukemia, B-cell prolymphocytic leukemia, lymphoplasmacyticlymphoma/Waldenström macroglobulinemia, splenic marginal zone lymphoma,plasma cell myeloma, plasmacytoma, extranodal marginal zone B celllymphoma, nodal marginal zone B cell lymphoma, mantle cell lymphoma,mediastinal (thymic) large B cell lymphoma, intravascular large B celllymphoma, primary effusion lymphoma, burkitt lymphoma/leukemia, orlymphomatoid granulomatosis. In some embodiments, where the subject issuffering from a cancer, an anti-cancer agent is administered to thesubject in addition to one of the above-mentioned compounds.

In some embodiments, provided herein is a method for treating athromboembolic disorder by administering to a subject in need thereof acomposition containing a therapeutically effective amount of at leastone compound having the structure of Formula (I)-(XVII). In someembodiments, the thromboembolic disorder is myocardial infarct, anginapectoris, reocclusion after angioplasty, restenosis after angioplasty,reocclusion after aortocoronary bypass, restenosis after aortocoronarybypass, stroke, transitory ischemia, a peripheral arterial occlusivedisorder, pulmonary embolism, or deep venous thrombosis.

In some embodiments are methods for treating inflammation comprisingadministering to the mammal at least once an effective amount of atleast one compound having the structure of Formula (I)-(XVII).

In some embodiments, the present invention provides methods for thetreatment of cancer comprising administering to the mammal at least oncean effective amount of at least one compound having the structure ofFormula (I)-(XVII). The type of cancer may include, but is not limitedto, pancreatic cancer and other solid or hematological tumors.

In some embodiments, the present invention provides methods for treatingrespiratory diseases comprising administering to the mammal at leastonce an effective amount of at least one compound having the structureFormula (I)-(XVII). In some embodiments, the respiratory disease isasthma. In some embodiments, the respiratory disease includes, but isnot limited to, adult respiratory distress syndrome and allergic(extrinsic) asthma, non-allergic (intrinsic) asthma, acute severeasthma, chronic asthma, clinical asthma, nocturnal asthma,allergen-induced asthma, aspirin-sensitive asthma, exercise-inducedasthma, isocapnic hyperventilation, child-onset asthma, adult-onsetasthma, cough-variant asthma, occupational asthma, steroid-resistantasthma, and seasonal asthma.

In some embodiments, the present invention provides methods forpreventing rheumatoid arthritis and osteoarthritis comprisingadministering to the mammal at least once an effective amount of atleast one compound having the structure of Formula (I)-(XVII).

In some embodiments, the present invention provides methods for treatinginflammatory responses of the skin comprising administering to themammal at least once an effective amount of at least one compound havingthe structure of Formula (I)-(XVII). Such inflammatory responses of theskin include, by way of example, dermatitis, contact dermatitis, eczema,urticaria, rosacea, and scarring. In another aspect are methods forreducing psoriatic lesions in the skin, joints, or other tissues ororgans, comprising administering to the mammal an effective amount of afirst compound having the structure of Formula (I)-(XVII)

In certain embodiments, the present invention discloses methods fortreating the following diseases or conditions comprising administeringto the mammal a compound of the invention. In some embodiments, thedisease or condition is ALL (Acute Lymphoblastic Lymphoma), DLBCL(Diffuse Large B-Cell Lymphoma), FL (Follicular Lymphoma), RCC (RenalCell Carcinoma), Childhoon Medulloblastoma, Glioblastoma, Pancreatictumor or cancer, Liver cancer (Hepatocellular Carcinoma), ProstateCancer (Myc), Triple Negative Breast (Myc), AML (Acute MyeloidLeukemia), or MDS (Myelo Dyslplastic Syndrome). In some embodiments, thedisease or condition is Early-onset Dystonia. In yet some embodiments,the disease or condition is Kabuki Syndrome.

In some embodiments, the disease or condition is p53 driven tumor.

P53 Driven tumors and Menin/MLL1

RUNX2 signaling pathway is one of survival signals specific to p53defective cancer cells. RUNX2 recruits the Menin/MLL1 epigenetic complexto induce the expression of MYC. Using small molecule irreversibleinhibitors of the Menin/MLL1 complex, targeting RUNX2/Menin/MLL1/MYCaxis is a feasible strategy for killing p53 defective cancer cells(Shih, et al., A RUNX2-Mediated Epigenetic Regulation of the Survival ofp53 Defective Cancer Cells. PLOS Genetics,doi.org/10.1371/journal.pgen.1005884, 2016).

In some embodiments, the disease or condition is MYC driven tumor.

MYC Driven Tumors and Menin/MLL1

MYC is documented to be involved broadly in many cancers, in which itsexpression is estimated to be elevated or deregulated in up to 70% ofhuman cancers. High levels of MYC expression have been linked toaggressive human prostate cancer and triple negative breast cancer(Gurel et al., Mod Pathol. 2008 September; 21(9):1156-67; Palaskas etal., Cancer Res. 2011 Aug. 1; 71(15):5164-74). Experimental models ofMyc-mediated tumorigenesis suggest that established tumors are addictedto Myc and that deregulated expression of Myc result in an addiction notonly to Myc but also to nutrients. These Myc-induced changes provide aunique opportunity for new therapeutic strategies. Notwithstanding thefact that normal proliferating cells (stem cell compartments and immunecells) also use MYC for renewal, many studies have focused on targetingMyc for cancer therapeutics. Strategies have emerged to inhibit MYCexpression, to interrupt Myc-Max dimerization, to inhibit Myc-Max DNAbinding, and to interfere with key Myc target genes (Dang et al. Cell.2012, 149(1): 22-35).

Menin's role in tumor suppression is cell-specific, Menin disruption inthe liver or haematopoetic system does not result in tumors. Importantto measure the concentration of the drug in endocrine tissue, livertissue, bone marrow, and Haematopoetic.

In any of the aforementioned embodiments are some embodiments in whichadministration is enteral, parenteral, or both, and wherein (a) aneffective amount of a provided compound is systemically administered tothe mammal; (b) an effective amount of a provided compound isadministered orally to the mammal; (c) an effective amount of a providedcompound is intravenously administered to the mammal; (d) an effectiveamount of a provided compound is administered by inhalation; (e) aneffective amount of a provided compound is administered by nasaladministration; or (f) an effective amount of a provided compound isadministered by injection to the mammal; (g) an effective amount of aprovided compound is administered topically (dermal) to the mammal; (h)an effective amount of a provided compound is administered by ophthalmicadministration; or (i) an effective amount of a provided compound isadministered rectally to the mammal.

In any of the aforementioned embodiments are some embodiments comprisingsingle administrations of an effective amount of a provided compound is,including some embodiments in which (i) a provided compound isadministered once; (ii) a provided compound is administered to themammal multiple times over the span of one day; (iii) continually; or(iv) continuously.

In any of the aforementioned embodiments are some embodiments comprisingmultiple administrations of an effective amount of a provided compound,including some embodiments in which (i) a provided compound isadministered in a single dose; (ii) the time between multipleadministrations is every 6 hours; (iii) a provided compound isadministered to the mammal every 8 hours. In some embodiments, themethod comprises a drug holiday, wherein the administration of thecompound is temporarily suspended or the dose of the compound beingadministered is temporarily reduced; at the end of the drug holiday,dosing of the compound is resumed. The length of the drug holiday canvary from 2 days to 1 year.

In any of the aforementioned embodiments involving the treatment ofproliferative disorders, including cancer, are some embodimentscomprising administering at least one additional agent selected from thegroup consisting of alemtuzumab, arsenic trioxide, asparaginase(pegylated or non-), bevacizumab, cetuximab, platinum-based compoundssuch as cisplatin, cladribine, daunorubicin/doxorubicin/idarubicin,irinotecan, fludarabine, 5-fluorouracil, gemtuzumab, methotrexate,Paclitaxel™, taxol, temozolomide, thioguanine, or classes of drugsincluding hormones (an antiestrogen, an antiandrogen, or gonadotropinreleasing hormone analogues, interferons such as alpha interferon,nitrogen mustards such as busulfan or melphalan or mechlorethamine,retinoids such as tretinoin, topoisomerase irreversible inhibitors suchas irinotecan or topotecan, tyrosine kinase irreversible inhibitors suchas gefinitinib or imatinib, or agents to treat signs or symptoms inducedby such therapy including allopurinol, filgrastim,granisetron/ondansetron/palonosetron, dronabinol.

In some embodiments, the compounds of Formula (I)-(XLIIIc) areirreversible inhibitors of Menin-MLL activity. In certain embodiments,such irreversible inhibitors have an IC₅₀ below 10 microM in enzymeassay. In some embodiments, a menin-MLL inhibitor has an IC₅₀ of lessthan 1 microM, and in some embodiments, less than 0.25 microM.

Other objects, features and advantages of the methods and compositionsdescribed herein will become apparent from the following detaileddescription. It should be understood, however, that the detaileddescription and the specific examples, while indicating specificembodiments, are given by way of illustration only, since variouschanges and modifications within the spirit and scope of the presentdisclosure will become apparent to those skilled in the art from thisdetailed description. The section headings used herein are fororganizational purposes only and are not to be construed as limiting thesubject matter described. All documents, or portions of documents, citedin the application including, but not limited to, patents, patentapplications, articles, books, manuals, and treatises are herebyexpressly incorporated by reference in their entirety for any purpose.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 shows effect of increasing concentrations of Compound 1 andMI-503 (0.027 μM-20 μM) on HL-60 cell proliferation after 4 daystreatment, as detected by the CellTiterGlo Cell viability assay. Eachdata point is the mean±SEM of data from the individual experimentperformed in duplicate

FIG. 2 shows effect of increasing concentrations of Compound 1 andMI-503 (0.027 μM-20 μM) on MV-4-11 cell proliferation after 4 daystreatment as detected by the CellTiterGlo Cell viability assay. Eachdata point is the mean±SEM of data from the individual experimentperformed in duplicate

FIG. 3 shows effect of increasing concentrations of Compound 1 andMI-503 (0.027 μM-20 μM) on MOLM-13 cell proliferation after 4 daystreatment as detected by the CellTiterGlo Cell viability assay. Eachdata point is the mean±SEM of data from the individual experimentperformed in duplicate.

FIG. 4 shows effect of increasing concentrations of Compound 10 onRS-411, HL-60, MOLM-13, and MV411 cell proliferation after 4, 7, 11, and14 days (T4, T7, T11, and T14) treatment as detected by the CellTiterGloCell viability assay. Each data point is the mean±SEM of data from theindividual experiment performed in duplicate.

FIG. 5 shows effect of increasing concentrations of Compound 13 onRS-411, HL-60, MOLM-13, and MV411 cell proliferation after 4, 7, 11, and14 days (T4, T7, T11, and T14) treatment as detected by the CellTiterGloCell viability assay. Each data point is the mean±SEM of data from theindividual experiment performed in duplicate.

FIG. 6 shows effect of increasing concentrations of Compound 15 onRS-411, HL-60, MOLM-13, and MV411 cell proliferation after 4, 7, 11, and14 days (T4, T7, T11, and T14) treatment as detected by the CellTiterGloCell viability assay. Each data point is the mean±SEM of data from theindividual experiment performed in duplicate.

FIG. 7 shows Long Term Proliferation Assay results of Compound 10.

FIG. 8 shows Long Term Proliferation Assay results of Compound 13,Compound 15, and Compound 23.

DETAILED DESCRIPTION OF THE INVENTION Certain Terminology

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as is commonly understood by one of skill in theart to which the claimed subject matter belongs. In the event that thereare a plurality of definitions for terms herein, those in this sectionprevail. Where reference is made to a URL or other such identifier oraddress, it is understood that such identifiers can change andparticular information on the internet can come and go, but equivalentinformation can be found by searching the internet. Reference theretoevidences the availability and public dissemination of such information.

It is to be understood that the foregoing general description and thefollowing detailed description are exemplary and explanatory only andare not restrictive of any subject matter claimed. In this application,the use of the singular includes the plural unless specifically statedotherwise. It must be noted that, as used in the specification and theappended claims, the singular forms “a,” “an” and “the” include pluralreferents unless the context clearly dictates otherwise. Use of the term“including” as well as other forms, such as “include”, “includes,” and“included,” is not limiting. Definition of standard chemistry terms maybe found in reference works, including Carey and Sundberg “AdvancedOrganic Chemistry 4^(TH) ED.” Vols. A (2000) and B (2001), Plenum Press,New York. Unless otherwise indicated, conventional methods of massspectroscopy, NMR, HPLC, protein chemistry, biochemistry, recombinantDNA techniques and pharmacology, within the skill of the art areemployed. Unless specific definitions are provided, the nomenclatureemployed in connection with, and the laboratory procedures andtechniques of, analytical chemistry, synthetic organic chemistry, andmedicinal and pharmaceutical chemistry described herein are those knownin the art. Standard techniques can be used for chemical syntheses,chemical analyses, pharmaceutical preparation, formulation, anddelivery, and treatment of patients. Standard techniques can be used forrecombinant DNA, oligonucleotide synthesis, and tissue culture andtransformation (e.g., electroporation, lipofection). Reactions andpurification techniques can be performed e.g., using kits ofmanufacturer's specifications or as commonly accomplished in the art oras described herein. The foregoing techniques and procedures can begenerally performed of conventional methods well known in the art and asdescribed in various general and more specific references that are citedand discussed throughout the present specification.

It is to be understood that the methods and compositions describedherein are not limited to the particular methodology, protocols, celllines, constructs, and reagents described herein and as such may vary.It is also to be understood that the terminology used herein is for thepurpose of describing particular embodiments only, and is not intendedto limit the scope of the methods and compositions described herein,which will be limited only by the appended claims.

All publications and patents mentioned herein are incorporated herein byreference in their entirety for the purpose of describing anddisclosing, for example, the constructs and methodologies that aredescribed in the publications, which might be used in connection withthe methods, compositions and compounds described herein. Thepublications discussed herein are provided solely for their disclosureprior to the filing date of the present application. Nothing herein isto be construed as an admission that the inventors described herein arenot entitled to antedate such disclosure by virtue of prior invention orfor any other reason.

“Alkyl” refers to a straight or branched hydrocarbon chain radicalconsisting solely of carbon and hydrogen atoms, containing nounsaturation, having from one to fifteen carbon atoms (e.g., C₁-C₁₅alkyl). In certain embodiments, an alkyl comprises one to thirteencarbon atoms (e.g., C₁-C₁₃ alkyl). In certain embodiments, an alkylcomprises one to eight carbon atoms (e.g., C₁-C₈ alkyl). In someembodiments, an alkyl comprises five to fifteen carbon atoms (e.g.,C₅-C₁₅ alkyl). In certain embodiments, an alkyl comprises five to eightcarbon atoms (e.g., C₅-C₈ alkyl). The alkyl is attached to the rest ofthe molecule by a single bond, for example, methyl (Me), ethyl (Et),n-propyl (n-pr), 1-methylethyl (iso-propyl or i-Pr), n-butyl (n-Bu),n-pentyl, 1,1-dimethylethyl (t-butyl, or t-Bu), 3-methylhexyl,2-methylhexyl, and the like. Unless stated otherwise specifically in thespecification, an alkyl group is optionally substituted as defined anddescribed below and herein.

The alkyl group could also be a “lower alkyl” having 1 to 6 carbonatoms.

As used herein, C₁-C_(x) includes C₁-C₂, C₁-C₃ . . . C₁-C_(x).

“Alkenyl” refers to a straight or branched hydrocarbon chain radicalgroup consisting solely of carbon and hydrogen atoms, containing atleast one double bond, and having from two to twelve carbon atoms. Incertain embodiments, an alkenyl comprises two to eight carbon atoms. Insome embodiments, an alkenyl comprises two to four carbon atoms. Thealkenyl is attached to the rest of the molecule by a single bond, forexample, ethenyl (i.e., vinyl), prop-1-enyl (i.e., allyl), but-1-enyl,pent-1-enyl, penta-1,4-dienyl, and the like. Unless stated otherwisespecifically in the specification, an alkenyl group is optionallysubstituted as defined and described below and herein.

“Alkynyl” refers to a straight or branched hydrocarbon chain radicalgroup consisting solely of carbon and hydrogen atoms, containing atleast one triple bond, having from two to twelve carbon atoms. Incertain embodiments, an alkynyl comprises two to eight carbon atoms. Insome embodiments, an alkynyl has two to four carbon atoms. The alkynylis attached to the rest of the molecule by a single bond, for example,ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Unlessstated otherwise specifically in the specification, an alkynyl group isoptionally substituted as defined and described below and herein.

“Alkylene” or “alkylene chain” refers to a straight or branched divalenthydrocarbon chain linking the rest of the molecule to a radical group,consisting solely of carbon and hydrogen, containing no unsaturation andhaving from one to twelve carbon atoms, for example, methylene,ethylene, propylene, n-butylene, and the like. The alkylene chain isattached to the rest of the molecule through a single bond and to theradical group through a single bond. The points of attachment of thealkylene chain to the rest of the molecule and to the radical group canbe through one carbon in the alkylene chain or through any two carbonswithin the chain. Unless stated otherwise specifically in thespecification, an alkylene chain is optionally substituted as definedand described below and herein.

“Alkenylene” or “alkenylene chain” refers to a straight or brancheddivalent hydrocarbon chain linking the rest of the molecule to a radicalgroup, consisting solely of carbon and hydrogen, containing at least onedouble bond and having from two to twelve carbon atoms, for example,ethenylene, propenylene, n-butenylene, and the like. The alkenylenechain is attached to the rest of the molecule through a double bond or asingle bond and to the radical group through a double bond or a singlebond. The points of attachment of the alkenylene chain to the rest ofthe molecule and to the radical group can be through one carbon or anytwo carbons within the chain. Unless stated otherwise specifically inthe specification, an alkenylene chain is optionally substituted asdefined and described below and herein. “Aryl” refers to a radicalderived from an aromatic monocyclic or multicyclic hydrocarbon ringsystem by removing a hydrogen atom from a ring carbon atom. The aromaticmonocyclic or multicyclic hydrocarbon ring system contains only hydrogenand carbon from six to eighteen carbon atoms, where at least one of therings in the ring system is fully unsaturated, i.e., it contains acyclic, delocalized (4n+2) π-electron system in accordance with theHückel theory. Aryl groups include, but are not limited to, groups suchas phenyl (Ph), fluorenyl, and naphthyl. Unless stated otherwisespecifically in the specification, the term “aryl” or the prefix “ar-”(such as in “aralkyl”) is meant to include aryl radicals optionallysubstituted as defined and described below and herein.

“Aralkyl” refers to a radical of the formula —R^(c)-aryl where R^(c) isan alkylene chain as defined above, for example, benzyl, diphenylmethyland the like. The alkylene chain part of the aralkyl radical isoptionally substituted as described above for an alkylene chain. Thearyl part of the aralkyl radical is optionally substituted as describedabove for an aryl group.

“Aralkenyl” refers to a radical of the formula —R^(d)-aryl where R^(d)is an alkenylene chain as defined above. The aryl part of the aralkenylradical is optionally substituted as described above for an aryl group.The alkenylene chain part of the aralkenyl radical is optionallysubstituted as defined above for an alkenylene group.

“Aralkynyl” refers to a radical of the formula —R^(e)-aryl, where R^(e)is an alkynylene chain as defined above. The aryl part of the aralkynylradical is optionally substituted as described above for an aryl group.The alkynylene chain part of the aralkynyl radical is optionallysubstituted as defined above for an alkynylene chain.

“Carbocyclyl” refers to a stable non-aromatic monocyclic or polycyclichydrocarbon radical consisting solely of carbon and hydrogen atoms,which includes fused or bridged ring systems, having from three tofifteen carbon atoms. In certain embodiments, a carbocyclyl comprisesthree to ten carbon atoms. In some embodiments, a carbocyclyl comprisesfive to seven carbon atoms. The carbocyclyl is attached to the rest ofthe molecule by a single bond. Carbocyclyl is optionally saturated,(i.e., containing single C—C bonds only) or unsaturated (i.e.,containing one or more double bonds or triple bonds.) A fully saturatedcarbocyclyl radical is also referred to as “cycloalkyl.” Examples ofmonocyclic cycloalkyls include, e.g., cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. An unsaturatedcarbocyclyl is also referred to as “cycloalkenyl.” Examples ofmonocyclic cycloalkenyls include, e.g., cyclopentenyl, cyclohexenyl,cycloheptenyl, and cyclooctenyl. Polycyclic carbocyclyl radicalsinclude, for example, adamantyl, norbornyl (i.e.,bicyclo[2.2.1]heptanyl), norbornenyl, decalinyl,7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. Unless otherwisestated specifically in the specification, the term “carbocyclyl” ismeant to include carbocyclyl radicals that are optionally substituted asdefined and described below and herein. “Halo” or “halogen” refers tobromo, chloro, fluoro or iodo substituents.

The terms “haloalkyl,” “haloalkenyl,” “haloalkynyl” and “haloalkoxy”include alkyl, alkenyl, alkynyl and alkoxy structures in which at leastone hydrogen is replaced with a halogen atom. In certain embodiments inwhich two or more hydrogen atoms are replaced with halogen atoms, thehalogen atoms are all the same as one another. In some embodiments inwhich two or more hydrogen atoms are replaced with halogen atoms, thehalogen atoms are not all the same as one another.

“Fluoroalkyl” refers to an alkyl radical, as defined above, that issubstituted by one or more fluoro radicals, as defined above, forexample, trifluoromethyl, difluoromethyl, 2,2,2-trifluoroethyl,1-fluoromethyl-2-fluoroethyl, and the like. The alkyl part of thefluoroalkyl radical is optionally substituted as defined above for analkyl group.

As used herein, the term “non-aromatic heterocycle”, “heterocycloalkyl”or “heteroalicyclic” refers to a non-aromatic ring wherein one or moreatoms forming the ring is a heteroatom. A “non-aromatic heterocycle” or“heterocycloalkyl” group refers to a cycloalkyl group that includes atleast one heteroatom selected from nitrogen, oxygen and sulfur. Theradicals may be fused with an aryl or heteroaryl. Heterocycloalkyl ringscan be formed by three to 14 ring atoms, such as three, four, five, six,seven, eight, nine, or more than nine atoms. Heterocycloalkyl rings canbe optionally substituted. In certain embodiments, non-aromaticheterocycles contain one or more carbonyl or thiocarbonyl groups suchas, for example, oxo- and thio-containing groups. Examples ofheterocycloalkyls include, but are not limited to, lactams, lactones,cyclic imides, cyclic thioimides, cyclic carbamates,tetrahydrothiopyran, 4H-pyran, tetrahydropyran, piperidine, 1,3-dioxin,1,3-dioxane, 1,4-dioxin, 1,4-dioxane, piperazine, 1,3-oxathiane,1,4-oxathiin, 1,4-oxathiane, tetrahydro-1,4-thiazine, 2H-1,2-oxazine,maleimide, succinimide, barbituric acid, thiobarbituric acid,dioxopiperazine, hydantoin, dihydrouracil, morpholine, trioxane,hexahydro-1,3,5-triazine, tetrahydrothiophene, tetrahydrofuran,pyrroline, pyrrolidine, pyrrolidone, pyrrolidione, pyrazoline,pyrazolidine, imidazoline, imidazolidine, 1,3-dioxole, 1,3-dioxolane,1,3-dithiole, 1,3-dithiolane, isoxazoline, isoxazolidine, oxazoline,oxazolidine, oxazolidinone, thiazoline, thiazolidine, and1,3-oxathiolane. Illustrative examples of heterocycloalkyl groups, alsoreferred to as non-aromatic heterocycles, include:

and the like. The term heteroalicyclic also includes all ring forms ofthe carbohydrates, including but not limited to the monosaccharides, thedisaccharides and the oligosaccharides. Depending on the structure, aheterocycloalkyl group can be a monoradical or a diradical (i.e., aheterocycloalkylene group).

“Heteroaryl” refers to a radical derived from a 3- to 18-memberedaromatic ring radical that comprises two to seventeen carbon atoms andfrom one to six heteroatoms selected from nitrogen, oxygen and sulfur.As used herein, the heteroaryl radical is a monocyclic, bicyclic,tricyclic or tetracyclic ring system, wherein at least one of the ringsin the ring system is fully unsaturated, i.e., it contains a cyclic,delocalized (4n+2) π-electron system in accordance with the Hückeltheory. Heteroaryl includes fused or bridged ring systems. In someembodiments, heteroaryl rings have five, six, seven, eight, nine, ormore than nine ring atoms. The heteroatom(s) in the heteroaryl radicalis optionally oxidized. One or more nitrogen atoms, if present, areoptionally quaternized. The heteroaryl is attached to the rest of themolecule through any atom of the ring(s). Examples of heteroarylsinclude, but are not limited to, azepinyl, acridinyl, benzimidazolyl,benzindolyl, 1,3-benzodioxolyl, benzofuranyl, benzooxazolyl,benzo[d]thiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl,benzo[b][1,4]oxazinyl, 1,4-benzodioxanyl, benzonaphthofuranyl,benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl,benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl(benzothiophenyl), benzothieno[3,2-d]pyrimidinyl, benzotriazolyl,benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl,cyclopenta[d]pyrimidinyl,6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl,5,6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cinnolinyl,6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazinyl, dibenzofuranyl,dibenzothiophenyl, furanyl, furanonyl, furo[3,2-c]pyridinyl,5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidinyl,5,6,7,8,9,10-hexahydrocycloocta[d]pyridazinyl,5,6,7,8,9,10-hexahydrocycloocta[d]pyridinyl, isothiazolyl, imidazolyl,indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl,isoquinolyl, indolizinyl, isoxazolyl,5,8-methano-5,6,7,8-tetrahydroquinazolinyl, naphthyridinyl,1,6-naphthyridinonyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl,5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl, 1-phenyl-1H-pyrrolyl,phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl,purinyl, pyrrolyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl, pyridinyl,pyrido[3,2-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrazinyl,pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl, quinoxalinyl,quinolinyl, isoquinolinyl, tetrahydroquinolinyl,5,6,7,8-tetrahydroquinazolinyl,5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl,6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidinyl,5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl,triazolyl, tetrazolyl, triazinyl, thieno[2,3-d]pyrimidinyl,thieno[3,2-d]pyrimidinyl, thieno[2,3-c]pridinyl, and thiophenyl (i.e.thienyl). Unless stated otherwise specifically in the specification, theterm “heteroaryl” is meant to include heteroaryl radicals as definedabove which are optionally substituted as defined and described belowand herein.

“N-heteroaryl” refers to a heteroaryl radical as defined abovecontaining at least one nitrogen and where the point of attachment ofthe heteroaryl radical to the rest of the molecule is through a nitrogenatom in the heteroaryl radical. An N-heteroaryl radical is optionallysubstituted as described above for heteroaryl radicals.

“C-heteroaryl” refers to a heteroaryl radical as defined above and wherethe point of attachment of the heteroaryl radical to the rest of themolecule is through a carbon atom in the heteroaryl radical. AC-heteroaryl radical is optionally substituted as described above forheteroaryl radicals.

“Heteroarylalkyl” refers to a radical of the formula —R^(c)-heteroaryl,where R^(c) is an alkylene chain as defined above. If the heteroaryl isa nitrogen-containing heteroaryl, the heteroaryl is optionally attachedto the alkyl radical at the nitrogen atom. The alkylene chain of theheteroarylalkyl radical is optionally substituted as defined above foran alkylene chain. The heteroaryl part of the heteroarylalkyl radical isoptionally substituted as defined above for a heteroaryl group.

“Sulfanyl” refers to the —S— radical.

“Sulfinyl” refers to the —S(═O)— radical.

“Sulfonyl” refers to the —S(═O)₂— radical.

“Amino” refers to the —NH₂ radical.

“Cyano” refers to the —CN radical.

“Nitro” refers to the —NO₂ radical.

“Oxa” refers to the —O— radical.

“Oxo” refers to the ═O radical.

“Imino” refers to the ═NH radical.

“Thioxo” refers to the ═S radical.

An “alkoxy” group refers to a (alkyl)O— group, where alkyl is as definedherein.

An “aryloxy” group refers to an (aryl)O— group, where aryl is as definedherein.

“Carbocyclylalkyl” means an alkyl radical, as defined herein,substituted with a carbocyclyl group. “Cycloalkylalkyl” means an alkylradical, as defined herein, substituted with a cycloalkyl group.Non-limiting cycloalkylalkyl groups include cyclopropylmethyl,cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, and the like.

As used herein, the terms “heteroalkyl” “heteroalkenyl” and“heteroalkynyl” include optionally substituted alkyl, alkenyl andalkynyl radicals in which one or more skeletal chain atoms is aheteroatom, e.g., oxygen, nitrogen, sulfur, silicon, phosphorus orcombinations thereof. The heteroatom(s) may be placed at any interiorposition of the heteroalkyl group or at the position at which theheteroalkyl group is attached to the remainder of the molecule. Examplesinclude, but are not limited to, —CH₂—O—CH₃, —CH₂—CH₂—O—CH₃,—CH₂—NH—CH₃, —CH₂—CH₂—NH—CH₃, —CH₂—N(CH₃)—CH₃, —CH₂—CH₂—NH—CH₃,—CH₂—CH₂—N(CH₃)—CH₃, —CH₂—S—CH₂—CH₃, —CH₂—CH₂, —S(O)—CH₃,—CH₂—CH₂—S(O)₂—CH₃, —CH═CH—O—CH₃, —Si(CH₃)₃, —CH₂—CH═N—OCH₃, and—CH═CH—N(CH₃)—CH₃. In addition, up to two heteroatoms may beconsecutive, such as, by way of example, —CH₂—NH—OCH₃ and—CH₂—O—Si(CH₃)₃.

The term “heteroatom” refers to an atom other than carbon or hydrogen.Heteroatoms are typically independently selected from among oxygen,sulfur, nitrogen, silicon and phosphorus, but are not limited to theseatoms. In embodiments in which two or more heteroatoms are present, thetwo or more heteroatoms can all be the same as one another, or some orall of the two or more heteroatoms can each be different from theothers.

The term “bond,” “direct bond” or “single bond” refers to a chemicalbond between two atoms, or two moieties when the atoms joined by thebond are considered to be part of larger substructure.

An “isocyanato” group refers to a —NCO group.

An “isothiocyanato” group refers to a —NCS group.

The term “moiety” refers to a specific segment or functional group of amolecule.

Chemical moieties are often recognized chemical entities embedded in orappended to a molecule.

A “thioalkoxy” or “alkylthio” group refers to a —S-alkyl group.

A “alkylthioalkyl” group refers to an alkyl group substituted with a—S-alkyl group.

As used herein, the term “acyloxy” refers to a group of formulaRC(═O)O—.

“Carboxy” means a —C(O)OH radical.

As used herein, the term “acetyl” refers to a group of formula—C(═O)CH₃.

“Acyl” refers to the group —C(O)R.

As used herein, the term “trihalomethanesulfonyl” refers to a group offormula X₃CS(═O)₂— where X is a halogen.

“Cyanoalkyl” means an alkyl radical, as defined herein, substituted withat least one cyano group.

As used herein, the term “N-sulfonamido” or “sulfonylamino” refers to agroup of formula RS(═O)₂NH—.

As used herein, the term “O-carbamyl” refers to a group of formula—OC(═O)NR₂.

As used herein, the term “N-carbamyl” refers to a group of formulaROC(═O)NH—.

As used herein, the term “O-thiocarbamyl” refers to a group of formula—OC(═S)NR₂.

As used herein, “N-thiocarbamyl” refers to a group of formulaROC(═S)NH—.

As used herein, the term “C-amido” refers to a group of formula—C(═O)NR₂.

“Aminocarbonyl” refers to a —CONH₂ radical.

As used herein, the term “N-amido” refers to a group of formulaRC(═O)NH—.

“Hydroxyalkyl” refers to an alkyl radical, as defined herein,substituted with at least one hydroxy group. Non-limiting examples of ahydroxyalkyl include, but are not limited to, hydroxymethyl,2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl,1-(hydroxymethyl)-2-methylpropyl, 2-hydroxybutyl, 3-hydroxybutyl,4-hydroxybutyl, 2,3-dihydroxypropyl, 1-(hydroxymethyl)-2-hydroxyethyl,2,3-dihydroxybutyl, 3,4-dihydroxybutyl and2-(hydroxymethyl)-3-hydroxypropyl.

“Alkoxyalkyl” refers to an alkyl radical, as defined herein, substitutedwith an alkoxy group, as defined herein.

An “alkenyloxy” group refers to a (alkenyl)O— group, where alkenyl is asdefined herein.

The term “alkylamine” refers to the —N(alkyl)_(x)H_(y) group, where xand y are selected from among x=1, y=1 and x=2, y=0. When x=2, the alkylgroups, taken together with the N atom to which they are attached, canoptionally form a cyclic ring system.

“Alkylaminoalkyl” refers to an alkyl radical, as defined herein,substituted with an alkylamine, as defined herein.

An “amide” is a chemical moiety with the formula —C(O)NHR or —NHC(O)R,where R is selected from among alkyl, cycloalkyl, aryl, heteroaryl(bonded through a ring carbon) and heteroalicyclic (bonded through aring carbon). An amide moiety may form a linkage between an amino acidor a peptide molecule and a compound described herein, thereby forming aprodrug. Any amine, or carboxyl side chain on the compounds describedherein can be amidified. The procedures and specific groups to make suchamides are known to those of skill in the art and can readily be foundin reference sources such as Greene and Wuts, Protective Groups inOrganic Synthesis, 3^(rd) Ed., John Wiley & Sons, New York, N.Y., 1999,which is incorporated herein by reference in its entirety.

The term “ester” refers to a chemical moiety with formula —COOR, where Ris selected from among alkyl, cycloalkyl, aryl, heteroaryl (bondedthrough a ring carbon) and heteroalicyclic (bonded through a ringcarbon). Any hydroxy, or carboxyl side chain on the compounds describedherein can be esterified. The procedures and specific groups to makesuch esters are known to those of skill in the art and can readily befound in reference sources such as Greene and Wuts, Protective Groups inOrganic Synthesis, 3^(rd) Ed., John Wiley & Sons, New York, N.Y., 1999,which is incorporated herein by reference in its entirety.

As used herein, the term “ring” refers to any covalently closedstructure. Rings include, for example, carbocycles (e.g., aryls andcycloalkyls), heterocycles (e.g., heteroaryls and non-aromaticheterocycles), aromatics (e.g. aryls and heteroaryls), and non-aromatics(e.g., cycloalkyls and non-aromatic heterocycles). Rings can beoptionally substituted. Rings can be monocyclic or polycyclic.

As used herein, the term “ring system” refers to one, or more than onering.

The term “membered ring” can embrace any cyclic structure. The term“membered” is meant to denote the number of skeletal atoms thatconstitute the ring. Thus, for example, cyclohexyl, pyridine, pyran andthiopyran are 6-membered rings and cyclopentyl, pyrrole, furan, andthiophene are 5-membered rings.

The term “fused” refers to structures in which two or more rings shareone or more bonds.

As described herein, compounds of the invention may be “optionallysubstituted”. In general, the term “substituted,” whether preceded bythe term “optionally” or not, means that one or more hydrogens of adesignated moiety are replaced with a suitable substituent. Unlessotherwise indicated, an “optionally substituted” group may have asuitable substituent at each substitutable position of the group, andwhen more than one position in any given structure may be substitutedwith more than one substituent selected from a specified group, thesubstituent may be either the same or different at every position.Combinations of substituents envisioned by this invention are preferablythose that result in the formation of stable or chemically feasiblecompounds. The term “stable,” as used herein, refers to compounds thatare not substantially altered when subjected to conditions to allow fortheir production, detection, and, in certain embodiments, theirrecovery, purification, and use for one or more of the purposesdisclosed herein.

Suitable monovalent substituents on a substitutable carbon atom of an“optionally substituted” group are independently halogen;—(CH₂)₀₋₄R^(o); —(CH₂)₀₋₄OR^(o); —O(CH₂)₀₋₄R^(o), —O—(CH₂)₀₋₄C(O)OR^(o);—(CH₂)₀₋₄CH(OR^(o))₂; —(CH₂)₀₋₄SR^(o); —(CH₂)₀₋₄Ph, which may besubstituted with R^(o); —(CH₂)₀₋₄O(CH₂)₀₋₁Ph which may be substitutedwith R^(o); —CH═CHPh, which may be substituted with R^(o);—(CH₂)₀₋₄O(CH₂)₀₋₁-pyridyl which may be substituted with R^(o); —NO₂;—CN; —N₃; —(CH₂)₀₋₄N(R^(o))₂; —(CH₂)₀₋₄N(R^(o))C(O)R^(o);—N(R^(o))C(S)R^(o); —(CH₂)₀₋₄N(R^(o))C(O)NR^(o) ₂; —N(R^(o))C(S)NR^(o)₂; —(CH₂)₀₋₄N(R^(o))C(O)OR^(o); —N(R^(o))N(R^(o))C(O)R^(o);—N(R^(o))N(R^(o))C(O)NR^(o) ₂; —N(R^(o))N(R^(o))C(O)OR^(o);—(CH₂)₀₋₄C(O)R^(o); —C(S)R^(o); —(CH₂)₀₋₄C(O)OR^(o);—(CH₂)₀₋₄C(O)SR^(o); —(CH₂)₀₋₄C(O)OSiR^(o) ₃; —(CH₂)₀₋₄OC(O)R^(o);—OC(O)(CH₂)₀₋₄SR—, —SC(S)SR^(o); —(CH₂)₀₋₄SC(O)R^(o);—(CH₂)₀₋₄C(O)NR^(o) ₂; —C(S)NR^(o) ₂; —C(S)SR^(o); —(CH₂)₀₋₄OC(O)NR^(o)₂; —C(O)N(OR^(o))R^(o); —C(O)C(O)R^(o); —C(O)CH₂C(O)R^(o);—C(NOR^(o))R^(o); —(CH₂)₀₋₄SSR^(o); —(CH₂)₀₋₄S(O)₂R^(o);—(CH₂)₀₋₄S(O)₂OR^(o); —(CH₂)₀₋₄OS(O)₂R^(o); —S(O)₂NR^(o) ₂;—(CH₂)₀₋₄S(O)R^(o); —N(R^(o))S(O)₂NR^(o) ₂; —N(R^(o))S(O)₂R^(o);—N(OR^(o))R^(o); —C(NH)NR^(o) ₂; —P(O)₂R^(o); —P(O)R^(o) ₂; —OP(O)R^(o)₂; —OP(O)(OR^(o))₂; SiR^(o) ₃; —(C₁₋₄ straight or branchedalkylene)O—N(R^(o))₂; or —(C₁₋₄ straight or branchedalkylene)C(O)O—N(R^(o))₂, wherein each R^(o) may be substituted asdefined below and is independently hydrogen, C₁₋₆ aliphatic, —CH₂Ph,—O(CH₂)₀₋₁Ph, —CH₂-(5-6 membered heteroaryl ring), or a 5-6-memberedsaturated, partially unsaturated, or aryl ring having 0-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, or,notwithstanding the definition above, two independent occurrences ofR^(o), taken together with their intervening atom(s), form a3-12-membered saturated, partially unsaturated, or aryl mono- orbicyclic ring having 0-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur, which may be substituted as defined below.

Suitable monovalent substituents on R^(o) (or the ring formed by takingtwo independent occurrences of R^(o) together with their interveningatoms), are independently halogen, —(CH₂)₀₋₂R^(•), -(haloR^(•)),—(CH₂)₀₋₂OH, —(CH₂)₀₋₂OR^(•), —(CH₂)₀₋₂CH(OR^(•))₂; —O(haloR^(•)), —CN,—N₃, —(CH₂)₀₋₂C(O)R^(•), —(CH₂)₀₋₂C(O)OH, —(CH₂)₀₋₂C(O)OR^(•),—(CH₂)₀₋₂SR^(•), —(CH₂)₀₋₂SH, —(CH₂)₀₋₂NH₂, —(CH₂)₀₋₂NHR^(•),—(CH₂)₀₋₂NR^(•) ₂, —NO₂, —SiR^(•) ₃, —OSiR^(•) ₃, —C(O)SR^(•), —(C₁₋₄straight or branched alkylene)C(O)OR^(•), or —SSR^(•) wherein each R^(•)is unsubstituted or where preceded by “halo” is substituted only withone or more halogens, and is independently selected from C₁₋₄ aliphatic,—CH₂Ph, —O(CH₂)₀₋₁Ph, or a 5-6-membered saturated, partiallyunsaturated, or aryl ring having 0-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur. Suitable divalent substituents on asaturated carbon atom of R^(o) include ═O and ═S.

Suitable divalent substituents on a saturated carbon atom of an“optionally substituted” group include the following: ═O, ═S, ═NNR*₂,═NNHC(O)R*, ═NNHC(O)OR*, ═NNHS(O)₂R*, ═NR*, ═NOR*, —O(C(R*₂))₂₋₃O—, or—S(C(R*₂))₂₋₃S—, wherein each independent occurrence of R* is selectedfrom hydrogen, C₁₋₆ aliphatic which may be substituted as defined below,or an unsubstituted 5-6-membered saturated, partially unsaturated, oraryl ring having 0-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur. Suitable divalent substituents that are bound tovicinal substitutable carbons of an “optionally substituted” groupinclude: —O(CR*₂)₂₋₃O—, wherein each independent occurrence of R* isselected from hydrogen, C₁₋₆ aliphatic which may be substituted asdefined below, or an unsubstituted 5-6-membered saturated, partiallyunsaturated, or aryl ring having 0-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur.

Suitable substituents on the aliphatic group of R* include halogen,—R^(•), -(haloR^(•)), —OH, —OR^(•), —O(haloR^(•)), —CN, —C(O)OH,—C(O)OR^(•), —NH₂, —NHR^(•), —NR^(•) ₂, or —NO₂, wherein each R^(•) isunsubstituted or where preceded by “halo” is substituted only with oneor more halogens, and is independently C₁₋₄ aliphatic, —CH₂Ph,—O(CH₂)₀₋₁Ph, or a 5-6-membered saturated, partially unsaturated, oraryl ring having 0-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur.

Suitable substituents on a substitutable nitrogen of an “optionallysubstituted” group include —R^(†), —NR^(†) ₂, —C(O)R^(†), —C(O)OR^(†),—C(O)C(O)R^(†), —C(O)CH₂C(O)R^(†), —S(O)₂R^(†), —S(O)₂NR^(†) ₂,—C(S)NR^(†) ₂, —C(NH)NR^(†) ₂, or —N(R^(†))S(O)₂R^(†); wherein eachR^(†) is independently hydrogen, C₁₋₆ aliphatic which may be substitutedas defined below, unsubstituted —OPh, or an unsubstituted 5-6-memberedsaturated, partially unsaturated, or aryl ring having 0-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, or,notwithstanding the definition above, two independent occurrences ofR^(†), taken together with their intervening atom(s) form anunsubstituted 3-12-membered saturated, partially unsaturated, or arylmono- or bicyclic ring having 0-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur.

Suitable substituents on the aliphatic group of R^(†) are independentlyhalogen, —R^(•), -(haloR^(•)), —OH, —OR^(•), —O(haloR^(•)), —CN,—C(O)OH, —C(O)OR^(•), —NH₂, —NHR^(•), —NR^(•) ₂, or —NO₂, wherein eachR^(•) is unsubstituted or where preceded by “halo” is substituted onlywith one or more halogens, and is independently C₁₋₄ aliphatic, —CH₂Ph,—O(CH₂)₀₋₁Ph, or a 5-6-membered saturated, partially unsaturated, oraryl ring having 0-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur.

The term “nucleophile” or “nucleophilic” refers to an electron richcompound, or moiety thereof.

The term “electrophile”, or “electrophilic” refers to an electron pooror electron deficient molecule, or moiety thereof. Examples ofelectrophiles include, but in no way are limited to, Michael acceptormoieties.

The term “acceptable” or “pharmaceutically acceptable”, with respect toa formulation, composition or ingredient, as used herein, means havingno persistent detrimental effect on the general health of the subjectbeing treated or does not abrogate the biological activity or propertiesof the compound, and is relatively nontoxic.

As used herein, “amelioration” of the symptoms of a particular disease,disorder or condition by administration of a particular compound orpharmaceutical composition refers to any lessening of severity, delay inonset, slowing of progression, or shortening of duration, whetherpermanent or temporary, lasting or transient that can be attributed toor associated with administration of the compound or composition.

“Bioavailability” refers to the percentage of the weight of compoundsdisclosed herein, such as, compounds of any of Formula (I)-(XLIIIc)dosed that is delivered into the general circulation of the animal orhuman being studied. The total exposure (AUC_((0-∞))) of a drug whenadministered intravenously is usually defined as 100% bioavailable (F%). “Oral bioavailability” refers to the extent to which compoundsdisclosed herein, such as, compounds of any of Formula (I)-(XLIIIc) areabsorbed into the general circulation when the pharmaceuticalcomposition is taken orally as compared to intravenous injection.

“Blood plasma concentration” refers to the concentration of compoundsdisclosed herein, such as, compounds of any of Formula (I)-(XLIIIc) inthe plasma component of blood of a subject. It is understood that theplasma concentration of compounds of any of Formula (I)-(XLIIIc) mayvary significantly between subjects, due to variability with respect tometabolism and/or possible interactions with other therapeutic agents.In accordance with some embodiments disclosed herein, the blood plasmaconcentration of the compounds of any of Formula (I)-(XLIIIc) may varyfrom subject to subject. Likewise, values such as maximum plasmaconcentration (C_(max)) or time to reach maximum plasma concentration(T_(max)), or total area under the plasma concentration time curve(AUC_((0-∞))) may vary from subject to subject. Due to this variability,the amount necessary to constitute “a therapeutically effective amount”of a compound of any of Formula (I)-(XLIIIc) may vary from subject tosubject.

The terms “co-administration” or the like, as used herein, are meant toencompass administration of the selected therapeutic agents to a singlepatient, and are intended to include treatment regimens in which theagents are administered by the same or different route of administrationor at the same or different time.

The terms “effective amount” or “therapeutically effective amount,” asused herein, refer to a sufficient amount of an agent or a compoundbeing administered which will relieve to some extent one or more of thesymptoms of the disease or condition being treated. The result can bereduction and/or alleviation of the signs, symptoms, or causes of adisease, or any other desired alteration of a biological system. Forexample, an “effective amount” for therapeutic uses is the amount of thecomposition including a compound as disclosed herein required to providea clinically significant decrease in disease symptoms without undueadverse side effects. An appropriate “effective amount” in anyindividual case may be determined using techniques, such as a doseescalation study. The term “therapeutically effective amount” includes,for example, a prophylactically effective amount. An “effective amount”of a compound disclosed herein is an amount effective to achieve adesired pharmacologic effect or therapeutic improvement without undueadverse side effects. It is understood that “an effect amount” or “atherapeutically effective amount” can vary from subject to subject, dueto variation in metabolism of the compound of any of Formula (I)-(XVII),age, weight, general condition of the subject, the condition beingtreated, the severity of the condition being treated, and the judgmentof the prescribing physician. By way of example only, therapeuticallyeffective amounts may be determined by routine experimentation,including but not limited to a dose escalation clinical trial.

The terms “enhance” or “enhancing” means to increase or prolong eitherin potency or duration a desired effect. By way of example, “enhancing”the effect of therapeutic agents refers to the ability to increase orprolong, either in potency or duration, the effect of therapeutic agentson during treatment of a disease, disorder or condition. An“enhancing-effective amount,” as used herein, refers to an amountadequate to enhance the effect of a therapeutic agent in the treatmentof a disease, disorder or condition. When used in a patient, amountseffective for this use will depend on the severity and course of thedisease, disorder or condition, previous therapy, the patient's healthstatus and response to the drugs, and the judgment of the treatingphysician.

The term “identical,” as used herein, refers to two or more sequences orsubsequences which are the same. In addition, the term “substantiallyidentical,” as used herein, refers to two or more sequences which have apercentage of sequential units which are the same when compared andaligned for maximum correspondence over a comparison window, ordesignated region as measured using comparison algorithms or by manualalignment and visual inspection. By way of example only, two or moresequences may be “substantially identical” if the sequential units areabout 60% identical, about 65% identical, about 70% identical, about 75%identical, about 80% identical, about 85% identical, about 90%identical, or about 95% identical over a specified region. Suchpercentages to describe the “percent identity” of two or more sequences.The identity of a sequence can exist over a region that is at leastabout 75-100 sequential units in length, over a region that is about 50sequential units in length, or, where not specified, across the entiresequence. This definition also refers to the complement of a testsequence. By way of example only, two or more polypeptide sequences areidentical when the amino acid residues are the same, while two or morepolypeptide sequences are “substantially identical” if the amino acidresidues are about 60% identical, about 65% identical, about 70%identical, about 75% identical, about 80% identical, about 85%identical, about 90% identical, or about 95% identical over a specifiedregion. The identity can exist over a region that is at least about75-100 amino acids in length, over a region that is about 50 amino acidsin length, or, where not specified, across the entire sequence of apolypeptide sequence. In addition, by way of example only, two or morepolynucleotide sequences are identical when the nucleic acid residuesare the same, while two or more polynucleotide sequences are“substantially identical” if the nucleic acid residues are about 60%identical, about 65% identical, about 70% identical, about 75%identical, about 80% identical, about 85% identical, about 90%identical, or about 95% identical over a specified region. The identitycan exist over a region that is at least about 75-100 nucleic acids inlength, over a region that is about 50 nucleic acids in length, or,where not specified, across the entire sequence of a polynucleotidesequence.

The term “isolated,” as used herein, refers to separating and removing acomponent of interest from components not of interest. Isolatedsubstances can be in either a dry or semi-dry state, or in solution,including but not limited to an aqueous solution. The isolated componentcan be in a homogeneous state or the isolated component can be a part ofa pharmaceutical composition that comprises additional pharmaceuticallyacceptable carriers and/or excipients. By way of example only, nucleicacids or proteins are “isolated” when such nucleic acids or proteins arefree of at least some of the cellular components with which it isassociated in the natural state, or that the nucleic acid or protein hasbeen concentrated to a level greater than the concentration of its invivo or in vitro production. Also, by way of example, a gene is isolatedwhen separated from open reading frames which flank the gene and encodea protein other than the gene of interest.

A “metabolite” of a compound disclosed herein is a derivative of thatcompound that is formed when the compound is metabolized. The term“active metabolite” refers to a biologically active derivative of acompound that is formed when the compound is metabolized. The term“metabolized,” as used herein, refers to the sum of the processes(including, but not limited to, hydrolysis reactions and reactionscatalyzed by enzymes, such as, oxidation reactions) by which aparticular substance is changed by an organism. Thus, enzymes mayproduce specific structural alterations to a compound. For example,cytochrome P450 catalyzes a variety of oxidative and reductive reactionswhile uridine diphosphate glucuronyl transferases catalyze the transferof an activated glucuronic-acid molecule to aromatic alcohols, aliphaticalcohols, carboxylic acids, amines and free sulfhydryl groups. Furtherinformation on metabolism may be obtained from The Pharmacological Basisof Therapeutics, 9th Edition, McGraw-Hill (1996). Metabolites of thecompounds disclosed herein can be identified either by administration ofcompounds to a host and analysis of tissue samples from the host, or byincubation of compounds with hepatic cells in vitro and analysis of theresulting compounds. Both methods are well known in the art. In someembodiments, metabolites of a compound are formed by oxidative processesand correspond to the corresponding hydroxy-containing compound. In someembodiments, a compound is metabolized to pharmacologically activemetabolites.

The term “modulate,” as used herein, means to interact with a targeteither directly or indirectly so as to alter the activity of the target,including, by way of example only, to enhance the activity of thetarget, to inhibit the activity of the target, to limit the activity ofthe target, or to extend the activity of the target.

As used herein, the term “modulator” refers to a compound that alters anactivity of a molecule. For example, a modulator can cause an increaseor decrease in the magnitude of a certain activity of a moleculecompared to the magnitude of the activity in the absence of themodulator. In certain embodiments, a modulator is an inhibitor, whichdecreases the magnitude of one or more activities of a molecule. Incertain embodiments, an inhibitor completely prevents one or moreactivities of a molecule. In certain embodiments, a modulator is anactivator, which increases the magnitude of at least one activity of amolecule. In certain embodiments the presence of a modulator results inan activity that does not occur in the absence of the modulator.

The term “irreversible inhibitor,” as used herein, refers to a compoundthat, upon contact with a target protein (e.g., menin) causes theformation of a new covalent bond with or within the protein, whereby oneor more of the target protein's biological activities (e.g.,phosphotransferase activity) is diminished or abolished notwithstandingthe subsequent presence or absence of the irreversible inhibitor. Incontrast, a reversible inhibitor compound upon contact with a targetprotein does not cause the formation of a new covalent bond with orwithin the protein and therefore can associate and dissociate from thetarget protein.

The term “irreversible inhibitor of menin-MLL protein-proteininteraction” as used herein, refers to an inhibitor of menin that canform a covalent bond with an amino acid residue of menin. In oneembodiment, the irreversible inhibitor of menin can form a covalent bondwith a Cys residue of menin; in particular embodiments, the irreversibleinhibitor can form a covalent bond with a Cys 329 residue (or a homologthereof) of menin.

The term “prophylactically effective amount,” as used herein, refersthat amount of a composition applied to a patient that will relieve tosome extent one or more of the symptoms of a disease, condition ordisorder being treated. In such prophylactic applications, such amountsmay depend on the patient's state of health, weight, and the like. It isconsidered well within the skill of the art for one to determine suchprophylactically effective amounts by routine experimentation,including, but not limited to, a dose escalation clinical trial.

As used herein, the term “selective binding compound” refers to acompound that selectively binds to any portion of one or more targetproteins.

As used herein, the term “selectively binds” refers to the ability of aselective binding compound to bind to a target protein, such as, forexample, menin, with greater affinity than it binds to a non-targetprotein. In certain embodiments, specific binding refers to binding to atarget with an affinity that is at least 10, 50, 100, 250, 500, 1000 ormore times greater than the affinity for a non-target.

As used herein, the term “selective modulator” refers to a compound thatselectively modulates a target activity relative to a non-targetactivity. In certain embodiments, specific modulator refers tomodulating a target activity at least 10, 50, 100, 250, 500, 1000 timesmore than a non-target activity.

The term “substantially purified,” as used herein, refers to a componentof interest that may be substantially or essentially free of othercomponents which normally accompany or interact with the component ofinterest prior to purification. By way of example only, a component ofinterest may be “substantially purified” when the preparation of thecomponent of interest contains less than about 30%, less than about 25%,less than about 20%, less than about 15%, less than about 10%, less thanabout 5%, less than about 4%, less than about 3%, less than about 2%, orless than about 1% (by dry weight) of contaminating components. Thus, a“substantially purified” component of interest may have a purity levelof about 70%, about 75%, about 80%, about 85%, about 90%, about 95%,about 96%, about 97%, about 98%, about 99% or greater.

The term “subject” or “patient” as used herein, refers to an animalwhich is the object of treatment, observation or experiment. By way ofexample only, a subject may be, but is not limited to, a mammalincluding, but not limited to, a human.

As used herein, the term “target activity” refers to a biologicalactivity capable of being modulated by a selective modulator. Certainexemplary target activities include, but are not limited to, bindingaffinity, signal transduction, enzymatic activity, tumor growth,inflammation or inflammation-related processes, and amelioration of oneor more symptoms associated with a disease or condition.

As used herein, the term “target protein” refers to a molecule or aportion of a protein capable of being bound by a selective bindingcompound. In certain embodiments, a target protein is menin.

The terms “treat,” “treating” or “treatment”, as used herein, includealleviating, abating or ameliorating a disease or condition symptoms,preventing additional symptoms, ameliorating or preventing theunderlying metabolic causes of symptoms, inhibiting the disease orcondition, e.g., arresting the development of the disease or condition,relieving the disease or condition, causing regression of the disease orcondition, relieving a condition caused by the disease or condition, orstopping the symptoms of the disease or condition. The terms “treat,”“treating” or “treatment”, include, but are not limited to, prophylacticand/or therapeutic treatments.

As used herein, the IC₅₀ refers to an amount, concentration or dosage ofa particular test compound that achieves a 50% inhibition of a maximalresponse, such as inhibition of menin-MLL, in an assay that measuressuch response.

As used herein, EC₅₀ refers to a dosage, concentration or amount of aparticular test compound that elicits a dose-dependent response at 50%of maximal expression of a particular response that is induced, provokedor potentiated by the particular test compound.

Methods described herein include administering to a subject in need acomposition containing a therapeutically effective amount of one or moreMenin-MLL inhibitor compounds described herein.

In some embodiments, methods described herein can be used to treat anautoimmune disease, which includes, but is not limited to, rheumatoidarthritis, psoriatic arthritis, osteoarthritis, Still's disease,juvenile arthritis, lupus, diabetes, myasthenia gravis, Hashimoto'sthyroiditis, Ord's thyroiditis, Graves' disease Sjögren's syndrome,multiple sclerosis, Guillain-Barre syndrome, acute disseminatedencephalomyelitis, Addison's disease, opsoclonus-myoclonus syndrome,ankylosing spondylitis, antiphospholipid antibody syndrome, aplasticanemia, autoimmune hepatitis, coeliac disease, Goodpasture's syndrome,idiopathic thrombocytopenic purpura, optic neuritis, scleroderma,primary biliary cirrhosis, Reiter's syndrome, Takayasu's arteritis,temporal arteritis, warm autoimmune hemolytic anemia, Wegener'sgranulomatosis, psoriasis, alopecia universalis, Behçet's disease,chronic fatigue, dysautonomia, endometriosis, interstitial cystitis,neuromyotonia, scleroderma, and vulvodynia.

In some embodiments, methods described herein can be used to treatheteroimmune conditions or diseases, which include, but are not limitedto graft versus host disease, transplantation, transfusion, anaphylaxis,allergies (e.g., allergies to plant pollens, latex, drugs, foods, insectpoisons, animal hair, animal dander, dust mites, or cockroach calyx),type I hypersensitivity, allergic conjunctivitis, allergic rhinitis, andatopic dermatitis.

In some embodiments, methods described herein can be used to treat aninflammatory disease, which includes, but is not limited to asthma,inflammatory bowel disease, appendicitis, blepharitis, bronchiolitis,bronchitis, bursitis, cervicitis, cholangitis, cholecystitis, colitis,conjunctivitis, cystitis, dacryoadenitis, dermatitis, dermatomyositis,encephalitis, endocarditis, endometritis, enteritis, enterocolitis,epicondylitis, epididymitis, fasciitis, fibrositis, gastritis,gastroenteritis, hepatitis, hidradenitis suppurativa, laryngitis,mastitis, meningitis, myelitis myocarditis, myositis, nephritis,oophoritis, orchitis, osteitis, otitis, pancreatitis, parotitis,pericarditis, peritonitis, pharyngitis, pleuritis, phlebitis,pneumonitis, pneumonia, proctitis, prostatitis, pyelonephritis,rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendonitis,tonsillitis, uveitis, vaginitis, vasculitis, and vulvitis.

In some embodiments, methods described herein can be used to treat acancer, e.g., B-cell proliferative disorders, which include, but are notlimited to diffuse large B cell lymphoma, follicular lymphoma, chroniclymphocytic lymphoma, chronic lymphocytic leukemia, B-cellprolymphocytic leukemia, lymphoplasmacytic lymphoma/Waldenströmmacroglobulinemia, splenic marginal zone lymphoma, plasma cell myeloma,plasmacytoma, extranodal marginal zone B cell lymphoma, nodal marginalzone B cell lymphoma, mantle cell lymphoma, mediastinal (thymic) large Bcell lymphoma, intravascular large B cell lymphoma, primary effusionlymphoma, burkitt lymphoma/leukemia, and lymphomatoid granulomatosis.

In some embodiments, methods described herein can be used to treatthromboembolic disorders, which include, but are not limited tomyocardial infarct, angina pectoris (including unstable angina),reocclusions or restenoses after angioplasty or aortocoronary bypass,stroke, transitory ischemia, peripheral arterial occlusive disorders,pulmonary embolisms, and deep venous thromboses.

Symptoms, diagnostic tests, and prognostic tests for each of theabove-mentioned conditions are known in the art. See, e.g., Harrison'sPrinciples of Internal Medicine©,” 16th ed., 2004, The McGraw-HillCompanies, Inc. Dey et al. (2006), Cytojournal 3(24), and the “RevisedEuropean American Lymphoma” (REAL) classification system (see, e.g., thewebsite maintained by the National Cancer Institute).

A number of animal models of are useful for establishing a range oftherapeutically effective doses of Menin-MLL inhibitor compounds fortreating any of the foregoing diseases.

For example, dosing of Menin-MLL inhibitor compounds for treating anautoimmune disease can be assessed in a mouse model of rheumatoidarthritis. In this model, arthritis is induced in Balb/c mice byadministering anti-collagen antibodies and lipopolysaccharide. SeeNandakumar et al. (2003), Am. J. Pathol 163:1827-1837.

In another example, dosing of Menin-MLL irreversible inhibitors for thetreatment of B-cell proliferative disorders can be examined in, e.g., ahuman-to-mouse xenograft model in which human B-cell lymphoma cells(e.g. Ramos cells) are implanted into immunodeficient mice (e.g., “nude”mice) as described in, e.g., Pagel et al. (2005), Clin Cancer Res11(13):4857-4866.

Animal models for treatment of thromboembolic disorders are also known.

The therapeutic efficacy of a provided compound for one of the foregoingdiseases can be optimized during a course of treatment. For example, asubject being treated can undergo a diagnostic evaluation to correlatethe relief of disease symptoms or pathologies to inhibition of in vivomenin-MLL activity achieved by administering a given dose of anMenin-MLL inhibitor.

Compounds

In the following description of Menin-MLL inhibitor compounds suitablefor use in the methods described herein, definitions of referred-tostandard chemistry terms may be found in reference works (if nototherwise defined herein), including Carey and Sundberg “AdvancedOrganic Chemistry 4th Ed.” Vols. A (2000) and B (2001), Plenum Press,New York. Unless otherwise indicated, conventional methods of massspectroscopy, NMR, HPLC, protein chemistry, biochemistry, recombinantDNA techniques and pharmacology, within the ordinary skill of the artare employedUnless specific definitions are provided, the nomenclatureemployed in connection with, and the laboratory procedures andtechniques of, analytical chemistry, synthetic organic chemistry, andmedicinal and pharmaceutical chemistry described herein are those knownin the art. Standard techniques can be used for chemical syntheses,chemical analyses, pharmaceutical preparation, formulation, anddelivery, and treatment of patients.

Menin-MLL inhibitor compounds can be used for the manufacture of amedicament for treating any of the foregoing conditions (e.g.,autoimmune diseases, inflammatory diseases, allergy disorders, B-cellproliferative disorders, Myeloid cell proliferative disorder, Lymphoidcell proliferative disorder, or thromboembolic disorders).

In some embodiments, the Menin-MLL inhibitor compound used for themethods described herein inhibits menin-MLL activity with an in vitroIC₅₀ of less than about 10 μM (e.g., less than about 1 μM, less thanabout 0.5 μM, less than about 0.4 μM, less than about 0.3 μM, less thanabout 0.1 μM, less than about 0.08 μM, less than about 0.06 μM, lessthan about 0.05 μM, less than about 0.04 μM, less than about 0.03 μM,less than about 0.02 μM, less than about 0.01 μM, less than about 0.008μM, less than about 0.006 μM, less than about 0.005 μM, less than about0.004 μM, less than about 0.003 μM, less than about 0.002 μM, less thanabout 0.001 μM, less than about 0.00099 μM, less than about 0.00098 μM,less than about 0.00097 μM, less than about 0.00096 μM, less than about0.00095 μM, less than about 0.00094 μM, less than about 0.00093 μM, lessthan about 0.00092 μM, or less than about 0.00090 μM).

In some embodiments, the Menin-MLL inhibitor compound selectivelyinhibits an activated form of its target menin.

Also described herein are methods for synthesizing such irreversibleinhibitors, methods for using such irreversible inhibitors in thetreatment of diseases (including diseases wherein inhibition ofmenin-MLL interaction provides therapeutic benefit to a patient havingthe disease). Further described are pharmaceutical compositions thatinclude an inhibitor of menin-MLL interaction. Specifically, describedherein are compounds and methods of use thereof to inhibit interactionof menin with MLL oncoproteins (e.g., MLL1, MLL2, MLL-fusiononcoproteins).

Specifically described herein are irreversible inhibitors of menin-MLLinteraction that form a covalent bond with a cysteine residue on menin.Further described herein are irreversible inhibitors of menin-MLLinteraction that form a covalent bond with a Cys329 residue on menin.Also described are pharmaceutical formulations that include airreversible inhibitor of menin.

The menin inhibitor compounds described herein are selective for meninhaving a cysteine residue in an amino acid sequence position of themenin protein that is homologous to the amino acid sequence position ofcysteine 329 in menin. Irreversible inhibitor compounds described hereininclude a Michael acceptor moiety.

Generally, a reversible or irreversible inhibitor compound of menin usedin the methods described herein is identified or characterized in an invitro assay, e.g., an acellular biochemical assay or a cellularfunctional assay. Such assays are useful to determine an in vitro IC₅₀for a reversible or irreversible menin inhibitor compound.

Further, covalent complex formation between menin and a candidateirreversible menin inhibitor is a useful indicator of irreversibleinhibition of menin that can be readily determined by a number ofmethods known in the art (e.g., mass spectrometry). For example, someirreversible menin-inhibitor compounds can form a covalent bond with Cys329 of menin (e.g., via a Michael reaction). See S. Xu et al. AngewandteChemie International Ed. 57(6), 1601-1605 (2017) (incorporated byreference in its entirety).

Described herein are compounds of any of Formulae (I)-(XIVc). Alsodescribed herein are pharmaceutically acceptable salts, pharmaceuticallyacceptable solvates, pharmaceutically active metabolites, andpharmaceutically acceptable prodrugs of such compounds. Pharmaceuticalcompositions that include at least one such compound or apharmaceutically acceptable salt, pharmaceutically acceptable solvate,pharmaceutically active metabolite or pharmaceutically acceptableprodrug of such compound, are provided. In some embodiments, whencompounds disclosed herein contain an oxidizable nitrogen atom, thenitrogen atom can be converted to an N-oxide by methods well known inthe art. In certain embodiments, isomers and chemically protected formsof compounds having a structure represented by any of Formula(I)-(XLIIIc) are also provided.

In some embodiments, provided herein are menin-MLL irreversibleinhibitors according to compounds of formula (I).

In some embodiments, the present invention provides a compound accordingto Formula (I) having the structure:

or a pharmaceutically acceptable salt thereof,wherein:

A is C or N;

Cy is substituted or unsubstituted

Q is N, —N(H)—, —O—, or —S—; Z is —CR^(5a)═ or —N═;

X is —NR^(3a)—, —C(R^(3b))₂—, or —O—;Y is a single bond, —NR^(3a)—, —C(R^(3b))₂—, or —O—;

W is —C(O)—, —S(O)—, or —S(O)₂—;

one of R¹ and R² is Cy²-N(H)C(O)—C(R^(6a))═C(R^(6b))(R^(6c)), orCH₂—Cy²-N(H)C(O)—C(R^(6a))═C(R^(6b))(R^(6c)); and other is H, C₁₋₆alkyl, C₁₋₆ haloalkyl, halo, or CN;Cy² is an optionally substituted group selected from phenyl, pyridyl, ora 4-7 membered heterocycloalkyl ring having 1-2 heteroatomsindependently selected from nitrogen, oxygen, or sulfur;each R^(3a), and R^(3b) is independently H or C₁₋₆ alkyl;each R^(4a) and R^(4b) is independently H, halo, CN, OR, —N(R)₂,—C(O)N(R)₂, —NRC(O)R, —SO₂R, —C(O)R, —CO₂R, or an optionally substitutedgroup selected from C₁₋₆ alkyl, C₃₋₇ cycloalkyl, a 4-7 memberedheterocycloalkyl ring having 1-2 heteroatoms independently selected fromnitrogen, oxygen, or sulfur, phenyl, an 8-10 membered bicyclic arylring, and a 5-6 membered heteroaryl ring having 1-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur;each R is independently H, or an optionally substituted group selectedfrom C₁₋₆ aliphatic, phenyl, an 8-10 membered bicyclic aryl ring, a 4-7membered saturated or partially unsaturated heterocyclic ring having 1-2heteroatoms independently selected from nitrogen, oxygen, or sulfur, anda 5-6 membered heteroaryl ring having 1-4 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur, or:two R groups on the same nitrogen are taken together with theirintervening atoms to form a 4-7 membered saturated, partiallyunsaturated, or heteroaryl ring having 0-3 heteroatoms, in addition tothe nitrogen, independently selected from nitrogen, oxygen, or sulfur;R^(5a) is H, C₁₋₆ alkyl, C₁₋₆ haloalkyl, halo, or CN;each R^(6a) and R^(6b) is independently H or C₁₋₆ alkyl; or R^(6a) andR^(6b) are joined together to form a bond;R^(6c) is H or substituted or unsubstituted C₁₋₆ alkyl;m is 1, 2, or 3; and n is 1, 2, 3, or 4.

In some embodiments, W is —S(O)—, or —S(O)₂—.

In some embodiments, W is —C(O)—.

In some embodiments, X is —NR^(3a)—; and Y is —C(R^(3b))₂—, —NR^(3b)—,or —O—.

In some embodiments, Y is a single bond, or —NR^(3a)—; and X is—C(R^(3b))₂—, —NR^(3b)— or —O—.

In some embodiments, each of X and Y is independently —NR^(3a)—.

In some embodiments, R^(3a) is H.

In some embodiments, R^(3b) is H or Me.

In some embodiments, each of X and Y is —N(H)—.

In some embodiments, —X—W—Y— is —N(H)—C(O)—N(H)—, —N(H)—C(O)—CH₂—,—CH₂—C(O)—N(H)—, —N(H)—S(O)—N(H)—, —N(H)—S(O)—CH₂—, —CH₂—S(O)—N(H)—,—N(H)—S(O)₂—N(H)—, —N(H)—S(O)₂—CH₂—, —CH₂—S(O)₂—N(H)—, or —N(H)—C(O)—.

In some embodiments, R¹ is Cy²-N(H)C(O)—C(R^(6a))═C(R^(6b))(R^(6c)), orCH₂—Cy²-N(H)C(O)—C(R^(6a))═C(R^(6b))(R^(6c)); and R² is H, halo,hydroxyl, CN, substituted or unsubstituted C₁₋₆alkyl, substituted orunsubstituted amino, or substituted or unsubstituted alkoxy.

In some embodiments, R¹ is Cy²-N(H)C(O)—C(R^(6a))═C(R^(6b))(R^(6c)), orCH₂—Cy²-N(H)C(O)—C(R^(6a))═C(R^(6b))(R^(6c)); and R² is H, Me, Et, i-Pr,CF₃, F, Cl, OMe, OEt, or CN.

In some embodiments, R¹ is Cy²-N(H)C(O)—C(R^(6a))═C(R^(6b))(R^(6c)), orCH₂—Cy²-N(H)C(O)—C(R^(6a))═C(R^(6b))(R^(6c)); and R² is H.

In some embodiments, R² is Cy²-N(H)C(O)—C(R^(6a))═C(R^(6b))(R^(6c)), orCH₂—Cy²-N(H)C(O)—C(R^(6a))═C(R^(6b))(R^(6c)); and R¹ is H, halo,hydroxyl, CN, substituted or unsubstituted C₁₋₆alkyl, substituted orunsubstituted amino, or substituted or unsubstituted alkoxy.

In some embodiments, R² is Cy²-N(H)C(O)—C(R^(6a))═C(R^(6b))(R^(6c)), orCH₂—Cy²-N(H)C(O)—C(R^(6a))═C(R^(6b))(R^(6c)); and R¹ is H, Me, Et, i-Pr,CF₃, F, Cl, OMe, OEt, or CN.

In some embodiments, R² is Cy²-N(H)C(O)—C(R^(6a))═C(R^(6b))(R^(6c)), orCH₂—Cy²-N(H)C(O)—C(R^(6a))═C(R^(6b))(R^(6c)); and R¹ is H.

The compound according claim 1, wherein —X—W—Y— is —N(H)—C(O)—; R¹ is—CH₂—Cy²-N(H)C(O)—C(R^(6a))═C(R^(6b))(R^(6c)); and R² is H.

In some embodiments, the compound is according to formula (XXI):

or a pharmaceutically acceptable salt thereof,wherein A, Cy, Cy², R^(4b), R^(6a), R^(6b), R^(6c), m, and n are asdescribed for formula (I); and each R⁸ and R⁹ is independently H, C₁₋₆alkyl, C₁₋₆ haloalkyl, halo, or CN.

In some embodiments, one of R⁸ and R⁹ is H, halo, hydroxyl, CN,substituted or unsubstituted C₁₋₆alkyl, substituted or unsubstitutedamino, or substituted or unsubstituted alkoxy; and the other is H.

In some embodiments, each R⁸ and R⁹ is H, or Me.

In some embodiments, each R⁸ and R⁹ is H.

In some embodiments, A is N.

In some embodiments, A is C.

In some embodiments, m is 1 or 2.

In some embodiments, n is 1 or 2.

In some embodiments, each R^(4a) is independently H, halo, hydroxyl, CN,substituted or unsubstituted C₁₋₆alkyl, substituted or unsubstitutedamino, or substituted or unsubstituted alkoxy.

In some embodiments, each R^(4a) is independently H, Me, Et, i-Pr, CF₃,F, Cl, OMe, OEt, or CN.

In some embodiments, each R^(4a) is H.

In some embodiments, each R^(4b) is independently H, halo, hydroxyl, CN,substituted or unsubstituted C₁₋₆alkyl, substituted or unsubstitutedamino, or substituted or unsubstituted alkoxy.

In some embodiments, each R^(4b) is independently H, Me, Et, i-Pr, CF₃,F, Cl, OMe, OEt, or CN.

In some embodiments, each R^(4b) is H.

In some embodiments, the compound is according to formula (IIa), (IIb),(IIc) or (IId):

or a pharmaceutically acceptable salt thereof.

In some embodiments, R² is H, Me, Et, i-Pr, CF₃, F, Cl, OMe, OEt, or CN.

In some embodiments, R² is H.

In some embodiments, the compound is according to formula (XXIIa) or(XXIIb):

or a pharmaceutically acceptable salt thereof; wherein Cy, Cy², R^(6a),R^(6b), or R^(6c) are as described for formula (I).

In some embodiments, the compound is according to formula (IIIa),(IIIb), (IIc) or (IIId):

or a pharmaceutically acceptable salt thereof.

In some embodiments, The compound according to claim 1, wherein thecompound is according to formula (XXXIIa), (XXXIIb), (XXXIIc), (XXXIId),(XXXIIe), or (XXXIIf):

or a pharmaceutically acceptable salt thereof.

In some embodiments, R¹ is H, Me, Et, i-Pr, CF₃, F, Cl, OMe, OEt, or CN.

In some embodiments, R¹ is H.

In some embodiments, wherein the compound is according to formula(XXXIIIa), (XXXIIIb), (XXXIIIc), (XXXIIId), (XXXIIIe), or (XXXIIIf):

or a pharmaceutically acceptable salt thereof.

In some embodiments, Cy² is substituted or unsubstituted Ph, pyridyl,azetidinyl, pyrrolidinyl, piperidinyl, or azepinyl.

In some embodiments, the compound is according to formula (IVa), or(IVb):

or a pharmaceutically acceptable salt thereof; and wherein p is 0, 1, 2,or 3.

In some embodiments, the compound is according to formula (XXIIIa) or(XXIIIb):

or a pharmaceutically acceptable salt thereof; and wherein p is 0, 1, 2,or 3.

In some embodiments, Cy is substituted or unsubstituted

In some embodiments, Cy is substituted or unsubstituted

In some embodiments, Q is —N(H)—.

In some embodiments, Q is —O—.

In some embodiments, Q is —S—.

In some embodiments, Z is —N═.

In some embodiments, Z is —CR^(5a)═.

In some embodiments, R^(5a) is H, Me, Et, i-Pr, Cl, F, CF₃, or CN.

In some embodiments, R^(5a) is H, Me, or F.

In some embodiments, R^(5a) is H.

In some embodiments, Z is —C(H)═.

In some embodiments, Cy is

wherein R⁷ is an optionally substituted group selected from a 4-7membered heterocycloalkyl ring having 1-2 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur, phenyl, an 8-10 memberedbicyclic aryl ring, and a 5-6 membered heteroaryl ring having 1-4heteroatoms independently selected from nitrogen, oxygen, or sulfur.

In some embodiments, Cy is substituted or unsubstituted

wherein R⁷ is an optionally substituted group selected from a 4-7membered heterocycloalkyl ring having 1-2 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur, phenyl, an 8-10 memberedbicyclic aryl ring, and a 5-6 membered heteroaryl ring having 1-4heteroatoms independently selected from nitrogen, oxygen, or sulfur.

In some embodiments, the compound is according to formula (Va), or (Vb):

or a pharmaceutically acceptable salt thereof; and wherein p is 0, 1, 2,or 3; and R⁷ is an optionally substituted group selected from a 4-7membered heterocycloalkyl ring having 1-2 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur, phenyl, an 8-10 memberedbicyclic aryl ring, and a 5-6 membered heteroaryl ring having 1-4heteroatoms independently selected from nitrogen, oxygen, or sulfur.

In some embodiments, the compound is according to formula (XXIVa), or(XXIVb):

or a pharmaceutically acceptable salt thereof; and wherein p is 0, 1, 2,or 3; and R⁷ is an optionally substituted group selected from a 4-7membered heterocycloalkyl ring having 1-2 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur, phenyl, an 8-10 memberedbicyclic aryl ring, and a 5-6 membered heteroaryl ring having 1-4heteroatoms independently selected from nitrogen, oxygen, or sulfur.

In some embodiments, the compound is according to formula (XXXIVa), or(XXXIVb):

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is according to formula (XXXVa), or(XXXVb):

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is according to formula (XXXVIa), or(XXXVIb):

or a pharmaceutically acceptable salt thereof.

In some embodiments, R⁷ is 4-7 membered heterocycloalkyl ring having 1-2heteroatoms independently selected from nitrogen, oxygen, or sulfursubstituted with Me, Et, or i-Pr.

In some embodiments, R⁷ is pyrrolidinyl, piperidinyl, piperazinyl, ormorpholinyl.

In some embodiments, R⁷ is morpholinyl.

In some embodiments, R⁷ is substituted or unsubstituted heteroaryl.

In some embodiments, R⁷ is substituted or unsubstituted pyridyl orpyrimidyl.

In some embodiments, R⁷ is unsubstituted pyridyl.

In some embodiments, R⁷ is pyridyl substituted with halo, hydroxyl, CN,substituted or unsubstituted C₁₋₆alkyl, substituted or unsubstitutedamino, or substituted or unsubstituted alkoxy.

In some embodiments, R⁷ is pyridyl substituted with Me, Et, i-Pr, OH,Cl, F, CF₃, CN, or NH₂.

In some embodiments, R⁷ is pyridyl substituted with Me, Et, i-Pr, Cl, F,CF₃, or CN.

In some embodiments, R⁷ is substituted or unsubstituted pyrrolyl,pyrazolyl, imidazolyl, oxazolyl, triazolyl, thiazolyl, oxadiazolyl, orthiadiazolyl.

In some embodiments, R⁷ is substituted or unsubstituted imidazolyl.

In some embodiments, R⁷ is imidazoyl substituted with Me, Et, i-Pr, Cl,F, CF₃, or CN.

In some embodiments, R⁷ is imidazoyl substituted with Me.

In some embodiments, the compound is according to formula (VIa) or(VIb):

or a pharmaceutically acceptable salt thereof; and wherein p is 0, 1, 2,or 3.

In some embodiments, the compound is according to formula (XXVa), or(XXVb):

or a pharmaceutically acceptable salt thereof; and wherein p is 0, 1, 2,or 3.

In some embodiments, p is 0, 1, or 2.

In some embodiments, R² is H or F.

In some embodiments, R² is H.

In some embodiments, the compound is according to formula (VIIa),(VIIb), or (VIIc):

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is according to formula (VIIIa),(VIIIb), or (VIIIc):

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is according to formula (XXVIa),(XXVIb), or

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is according to formula (XXXVIIa), or(XXXVIIb):

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is according to formula (XXXVIIIa), or(XXXVIIIb):

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is according to formula (XXXIXa), or(XXXIXb):

or a pharmaceutically acceptable salt thereof.

In some embodiments, each of R^(6a), R^(6b), and R^(6c) is H.

In some embodiments, each of R^(6a), and R^(6b) is H; and R^(6c) issubstituted or unsubstituted alkyl.

In some embodiments, each of R^(6a), and R^(6b) is H; and R^(6c) isunsubstituted alkyl.

In some embodiments, each of R^(6a), and R^(6b) is H; and R^(6c) is Me,or Et.

In some embodiments, each of R^(6a), and R^(6b) is H; and R^(6c) isalkyl substituted with amino, alkylamino or dialkylamino.

In some embodiments, each of R^(6a), and R^(6b) is H; and R^(6c) isalkyl substituted with dimethylamino.

In some embodiments, each of R^(6a), and R^(6b) is H; and R^(6c) is—CH₂NMe₂.

In some embodiments, R^(6a), and R^(6b) form a bond; and R^(6c) is H orsubstituted or unsubstituted alkyl.

In some embodiments, R^(6a), and R^(6b) form a bond; and R^(6c) is Me.

In some embodiments, the compound is according to formula (IXa), (IXb),or (IXc):

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is according to formula (Xa), (Xb), or(Xc):

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is according to formula (XIa), (XIb),or (XIc):

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is according to formula (XIIa),(XIIb), or (XIIc):

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is according to formula (XIIIa),(XIIIb), or (XIIIc):

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is according to formula (XIVa),(XIVb), or (XIVc):

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is according to formula (XV):

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is according to formula (XVI):

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is according to formula (XVII):

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is according to formula (XXVIIa),(XXVIIb), or (XXVIIc):

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is according to formula (XXVIIIa),(XXVIIIb), or (XXVIIIc):

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is according to formula (XXIXa),(XXIXb), or XXIXc):

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is according to formula (XLa), (XLb),or (XLc):

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is according to formula (XLIa),(XLIb), or (XLIc):

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is according to formula (XLIa),(XLIb), or (XLIc):

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is according to formula (XLIIa),(XLIIb), or (XLIIc).

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is according to formula (XLIIIa),(XLIIIb), or (XLIIIc).

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound is according to formula (XLIIa).

In some embodiments, the compound is according to formula (XLIIIa).

Embodiments of the compounds of Formula (I) displayed improved potencyagainst menin-MLL with IC₅₀ values of as low as less than 1 nM or lessthan 0.1 nM, and/or high occupancy of active site of menin (e.g., morethan 50%, 70% or 90% occupancy) at low dosages of below 5 mg/kg (e.g.,at or below 3 mg/kg) when administered in vivo (e.g., in rats).

In some embodiments, the present invention provides, a pharmaceuticalcomposition comprising a compound according to formula (I).

In some embodiments, the present invention provides, a pharmaceuticalcomposition comprising a therapeutically effective amount of a compoundof formula (I), and a pharmaceutically acceptable excipient.

In some embodiments, the pharmaceutical composition is formulated for aroute of administration selected from oral administration, parenteraladministration, buccal administration, nasal administration, topicaladministration, or rectal administration.

In some embodiments, the present invention provides, methods fortreating an autoimmune disease or condition comprising administering toa patient in need the pharmaceutical composition of the presentinvention.

In some embodiments, the autoimmune disease is selected from rheumatoidarthritis or lupus.

In some embodiments, the present invention provides, methods fortreating a heteroimmune disease or condition comprising administering toa patient in need the pharmaceutical composition of the presentinvention.

In some embodiments, the present invention provides, for treating acancer comprising administering to a patient in need the pharmaceuticalcomposition the present invention.

In some embodiments, the cancer is a B-cell proliferative disorder.

In some embodiments, the B-cell proliferative disorder is diffuse largeB cell lymphoma, follicular lymphoma or chronic lymphocytic leukemia. Insome embodiments, the disorder is Myeloid leukemia. In some embodiments,the disorder is AML. In some embodiments, the B-cell proliferativedisorder is Lymphoid leukemia. In some embodiments, the disorder is ALL.In some embodiments, the disorder is Soft Tissue tumors. In someembodiments, the tumor is Glioblastoma. In some embodiments, the tumoris pancreatic tumor. In some embodiments, the disorder is Renal CellCancer.

In some embodiments, the present invention provides, methods fortreating mastocytosis comprising administering to a patient in need thepharmaceutical composition of the present invention.

In some embodiments, the present invention provides, methods fortreating osteoporosis or bone resorption disorders comprisingadministering to a patient in need the pharmaceutical composition of thepresent invention.

In some embodiments, the present invention provides, methods or treatingan inflammatory disease or condition comprising administering to apatient in need the pharmaceutical composition of the present invention.

In some embodiments, the present invention provides, methods fortreating lupus comprising administering to a subject in need thereof acomposition containing a therapeutically effective amount of a compoundof formula (I) that is inhibitor of menin-MLL interaction.

In some embodiments, the present invention provides methods for treatinga heteroimmune disease or condition comprising administering to asubject in need thereof a composition containing a therapeuticallyeffective amount of a compound of formula (I) that is inhibitor ofmenin-MLL interaction.

In some embodiments, the present invention provides, methods fortreating diffuse large B cell lymphoma, follicular lymphoma or chroniclymphocytic leukemia comprising administering to a subject in needthereof a composition containing a therapeutically effective amount of acompound of formula (I) that is inhibitor of the menin-MLL interaction.

In some embodiments, the present invention provides methods for treatingmastocytosis, comprising administering to a subject in need thereof acomposition containing a therapeutically effective amount of a compoundof formula (I) that is inhibitor of menin-MLL interaction.

In some embodiments, the present invention provides methods for treatingosteoporosis or bone resorption disorders comprising administering to asubject in need thereof a composition containing a therapeuticallyeffective amount of a compound of formula (I) that is inhibitor ofmenin-MLL interaction.

In some embodiments, the present invention provides methods for treatingan inflammatory disease or condition comprising administering to asubject in need thereof a composition containing a therapeuticallyeffective amount of a compound of formula (I) that is inhibitor ofmenin-MLL interaction.

In some embodiments, the present invention provides, a pharmaceuticalcomposition comprising a pharmaceutically acceptable carrier and apharmaceutically effective amount of a compound according to any one ofthe formulas described herein. In some embodiments, the compound isaccording to any one of Formula (I)-(XVII).

In some embodiments, the pharmaceutical composition is formulated for aroute of administration selected from oral administration, parenteraladministration, buccal administration, nasal administration, topicaladministration, or rectal administration.

In some embodiments, the carrier is a parenteral carrier.

In some embodiments, the carrier is an oral carrier.

In some embodiments, the carrier is a topical carrier.

Any combination of the groups described above for the various variablesis contemplated herein. It is understood that substituents andsubstitution patterns on the compounds provided herein can be selectedby one of ordinary skill in the art to provide compounds that arechemically stable and that can be synthesized by techniques known in theart, as well as those set forth herein.

Further representative embodiments of compounds of Formula (I), includecompounds listed in Table 1, or a solvate or a pharmaceuticallyacceptable salt thereof.

Throughout the specification, groups and substituents thereof can bechosen by one skilled in the field to provide stable moieties andcompounds.

In some embodiments, the compounds of Formula (I)-(XLIIIc) inhibitmenin-MLL. In some embodiments, the compounds of Formula (I)-(XLIIIc)are used to treat patients suffering from menin-MLL-dependent ormenin-MLL interaction mediated conditions or diseases, including, butnot limited to, cancer, autoimmune and other inflammatory diseases.

In some embodiments, the compounds of Formula (I)-(XLIIIc) inhibitmenin-MLL interaction. In some embodiments, the compounds of Formula(I)-(XLIIIc) are used to treat patients suffering from menin-MLLinteraction-dependent or menin-MLL interaction mediated conditions ordiseases, including, but not limited to, cancer, autoimmune and otherinflammatory diseases.

Preparation of Compounds

Compounds of any of Formula (I)-(XLIIIc) may be synthesized usingstandard synthetic reactions known to those of skill in the art or usingmethods known in the art. The reactions can be employed in a linearsequence to provide the compounds or they may be used to synthesizefragments which are subsequently joined by the methods known in the art.

Described herein are compounds that inhibit the activity of menin-MLL,and processes for their preparation. Also described herein arepharmaceutically acceptable salts, pharmaceutically acceptable solvates,pharmaceutically active metabolites and pharmaceutically acceptableprodrugs of such compounds. Pharmaceutical compositions that include atleast one such compound or a pharmaceutically acceptable salt,pharmaceutically acceptable solvate, pharmaceutically active metaboliteor pharmaceutically acceptable prodrug of such compound, are provided.

The starting material used for the synthesis of the compounds describedherein may be synthesized or can be obtained from commercial sources,such as, but not limited to, Aldrich Chemical Co. (Milwaukee, Wis.),Bachem (Torrance, Calif.), or Sigma Chemical Co. (St. Louis, Mo.). Thecompounds described herein, and other related compounds having differentsubstituents can be synthesized using techniques and materials known tothose of skill in the art, such as described, for example, in March,Advanced Organic Chemistry 4^(th) Ed., (Wiley 1992); Carey and Sundberg,Advanced Organic Chemistry 4^(th) Ed., Vols. A and B (Plenum 2000,2001); Green and Wuts, Protective Groups in Organic Synthesis 3^(rd)Ed., (Wiley 1999); Fieser and Fieser's Reagents for Organic Synthesis,Volumes 1-17 (John Wiley and Sons, 1991); Rodd's Chemistry of CarbonCompounds, Volumes 1-5 and Supplementals (Elsevier Science Publishers,1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991); andLarock's Comprehensive Organic Transformations (VCH Publishers Inc.,1989). (all of which are incorporated by reference in their entirety).Additional methods for the synthesis of compounds described herein maybe found in International Patent Publication No. WO 01/01982901, Arnoldet al. Bioorganic & Medicinal Chemistry Letters 10 (2000) 2167-2170;Burchat et al. Bioorganic & Medicinal Chemistry Letters 12 (2002)1687-1690. General methods for the preparation of compound as disclosedherein may be derived from known reactions in the field, and thereactions may be modified by the use of appropriate reagents andconditions, as would be recognized by the skilled person, for theintroduction of the various moieties found in the formulae as providedherein.

The products of the reactions may be isolated and purified, if desired,using conventional techniques, including, but not limited to,filtration, distillation, crystallization, chromatography and the like.Such materials may be characterized using conventional means, includingphysical constants and spectral data.

Compounds described herein may be prepared as a single isomer or amixture of isomers.

In some embodiments, representative compounds of Formula (I) areprepared according to synthetic schemes depicted herein.

Further Forms of Compounds

Compounds disclosed herein have a structure of Formula (I)-(XLIIIc). Itis understood that when reference is made to compounds described herein,it is meant to include compounds of any of Formula (I)-(XLIIIc) as wellas to all of the specific compounds that fall within the scope of thesegeneric formulae, unless otherwise indicated.

Compounds described herein may possess one or more stereocenters andeach center may exist in the R or S configuration. Compounds presentedherein include all diastereomeric, enantiomeric, and epimeric forms aswell as the appropriate mixtures thereof. Stereoisomers may be obtained,if desired, by methods known in the art as, for example, the separationof stereoisomers by chiral chromatographic columns.

Diastereomeric mixtures can be separated into their individualdiastereomers on the basis of their physical chemical differences bymethods known, for example, by chromatography and/or fractionalcrystallization. In some embodiments, enantiomers can be separated bychiral chromatographic columns. In some embodiments, enantiomers can beseparated by converting the enantiomeric mixture into a diastereomericmixture by reaction with an appropriate optically active compound (e.g.,alcohol), separating the diastereomers and converting (e.g.,hydrolyzing) the individual diastereomers to the corresponding pureenantiomers. All such isomers, including diastereomers, enantiomers, andmixtures thereof are considered as part of the compositions describedherein.

Methods and formulations described herein include the use of N-oxides,crystalline forms (also known as polymorphs), or pharmaceuticallyacceptable salts of compounds described herein, as well as activemetabolites of these compounds having the same type of activity. In somesituations, compounds may exist as tautomers. All tautomers are includedwithin the scope of the compounds presented herein. In addition,compounds described herein can exist in unsolvated as well as solvatedforms with pharmaceutically acceptable solvents such as water, ethanol,and the like. Solvated forms of compounds presented herein are alsoconsidered to be disclosed herein.

Compounds of any of Formula (I)-(XLIIIc) in unoxidized form can beprepared from N-oxides of compounds of any of Formula (I)-(XLIIIc) bytreating with a reducing agent, such as, but not limited to, sulfur,sulfur dioxide, triphenyl phosphine, lithium borohydride, sodiumborohydride, phosphorus trichloride, tribromide, or the like in asuitable inert organic solvent, such as, but not limited to,acetonitrile, ethanol, aqueous dioxane, or the like at 0 to 80° C.

In some embodiments, compounds described herein are prepared asprodrugs. A “prodrug” refers to an agent that is converted into theparent drug in vivo. Prodrugs are often useful because, in somesituations, they may be easier to administer than the parent drug. Theymay, for instance, be bioavailable by oral administration whereas theparent is not. The prodrug may also have improved solubility inpharmaceutical compositions over the parent drug. An example, withoutlimitation, of a prodrug would be a compound described herein, which isadministered as an ester (the “prodrug”) to facilitate transmittalacross a cell membrane where water solubility is detrimental to mobilitybut which then is metabolically hydrolyzed to the carboxylic acid, theactive entity, once inside the cell where water-solubility isbeneficial. A further example of a prodrug might be a short peptide(polyaminoacid) bonded to an acid group where the peptide is metabolizedto reveal the active moiety. In certain embodiments, upon in vivoadministration, a prodrug is chemically converted to the biologically,pharmaceutically or therapeutically active form of the compound. Incertain embodiments, a prodrug is enzymatically metabolized by one ormore steps or processes to the biologically, pharmaceutically ortherapeutically active form of the compound. To produce a prodrug, apharmaceutically active compound is modified such that the activecompound will be regenerated upon in vivo administration. The prodrugcan be designed to alter the metabolic stability or the transportcharacteristics of a drug, to mask side effects or toxicity, to improvethe flavor of a drug or to alter other characteristics or properties ofa drug. By virtue of knowledge of pharmacodynamic processes and drugmetabolism in vivo, those of skill in this art, once a pharmaceuticallyactive compound is known, can design prodrugs of the compound. (see, forexample, Nogrady (1985) Medicinal Chemistry A Biochemical Approach,Oxford University Press, New York, pages 388-392; Silverman (1992), TheOrganic Chemistry of Drug Design and Drug Action, Academic Press, Inc.,San Diego, pages 352-401, Saulnier et al., (1994), Bioorganic andMedicinal Chemistry Letters, Vol. 4, p. 1985).

Prodrug forms of the herein described compounds, wherein the prodrug ismetabolized in vivo to produce a derivative as set forth herein areincluded within the scope of the claims. In some cases, some of theherein-described compounds may be a prodrug for another derivative oractive compound.

Prodrugs are often useful because, in some situations, they may beeasier to administer than the parent drug. They may, for instance, bebioavailable by oral administration whereas the parent is not. Theprodrug may also have improved solubility in pharmaceutical compositionsover the parent drug. Prodrugs may be designed as reversible drugderivatives, for use as modifiers to enhance drug transport tosite-specific tissues. In some embodiments, the design of a prodrugincreases the effective water solubility. See, e.g., Fedorak et al., Am.J. Physiol., 269:G210-218 (1995); McLoed et al., Gastroenterol,106:405-413 (1994); Hochhaus et al., Biomed. Chrom., 6:283-286 (1992);J. Larsen and H. Bundgaard, Int. J. Pharmaceutics, 37, 87 (1987); J.Larsen et al., Int. J. Pharmaceutics, 47, 103 (1988); Sinkula et al., J.Pharm. Sci., 64:181-210 (1975); T. Higuchi and V. Stella, Pro-drugs asNovel Delivery Systems, Vol. 14 of the A.C.S. Symposium Series; andEdward B. Roche, Bioreversible Carriers in Drug Design, AmericanPharmaceutical Association and Pergamon Press, 1987, all incorporatedherein in their entirety.

Sites on the aromatic ring portion of compounds of any of Formula(I)-(XLIIIc) can be susceptible to various metabolic reactions,therefore incorporation of appropriate substituents on the aromatic ringstructures, such as, by way of example only, halogens can reduce,minimize or eliminate this metabolic pathway.

Compounds described herein include isotopically-labeled compounds, whichare identical to those recited in the various formulas and structurespresented herein, but for the fact that one or more atoms are replacedby an atom having an atomic mass or mass number different from theatomic mass or mass number usually found in nature. Examples of isotopesthat can be incorporated into the present compounds include isotopes ofhydrogen, carbon, nitrogen, oxygen, fluorine and chlorine, such as ²H,³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³⁵S, ¹⁸F, ³⁶Cl, respectively. Certainisotopically-labeled compounds described herein, for example those intowhich radioactive isotopes such as ³H and ¹⁴C are incorporated, areuseful in drug and/or substrate tissue distribution assays. Further,substitution with isotopes such as deuterium, i.e., ²H, can affordcertain therapeutic advantages resulting from greater metabolicstability, for example increased in vivo half-life or reduced dosagerequirements.

In additional or some embodiments, the compounds described herein aremetabolized upon administration to an organism in need to produce ametabolite that is then used to produce a desired effect, including adesired therapeutic effect.

Compounds described herein may be formed as, and/or used as,pharmaceutically acceptable salts. The type of pharmaceutical acceptablesalts, include, but are not limited to: (1) acid addition salts, formedby reacting the free base form of the compound with a pharmaceuticallyacceptable: inorganic acid such as hydrochloric acid, hydrobromic acid,sulfuric acid, nitric acid, phosphoric acid, metaphosphoric acid, andthe like; or with an organic acid such as acetic acid, propionic acid,hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid,lactic acid, malonic acid, succinic acid, malic acid, maleic acid,fumaric acid, trifluoroacetic acid, tartaric acid, citric acid, benzoicacid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid,methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid,2-hydroxyethanesulfonic acid, benzenesulfonic acid, toluenesulfonicacid, 2-naphthalenesulfonic acid,4-methylbicyclo-[2.2.2]oct-2-ene-1-carboxylic acid, glucoheptonic acid,4,4′-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionicacid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuricacid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylicacid, stearic acid, muconic acid, and the like; (2) salts formed when anacidic proton present in the parent compound either is replaced by ametal ion, e.g., an alkali metal ion (e.g. lithium, sodium, potassium),an alkaline earth ion (e.g. magnesium, or calcium), or an aluminum ion;or coordinates with an organic base. Acceptable organic bases includeethanolamine, diethanolamine, triethanolamine, tromethamine,N-methylglucamine, and the like. Acceptable inorganic bases includealuminum hydroxide, calcium hydroxide, potassium hydroxide, sodiumcarbonate, sodium hydroxide, and the like.

The corresponding counterions of the pharmaceutically acceptable saltsmay be analyzed and identified using various methods including, but notlimited to, ion exchange chromatography, ion chromatography, capillaryelectrophoresis, inductively coupled plasma, atomic absorptionspectroscopy, mass spectrometry, or any combination thereof.

The salts are recovered by using at least one of the followingtechniques: filtration, precipitation with a non-solvent followed byfiltration, evaporation of the solvent, or, in the case of aqueoussolutions, lyophilization.

It should be understood that a reference to a pharmaceuticallyacceptable salt includes the solvent addition forms or crystal formsthereof, particularly solvates or polymorphs. Solvates contain eitherstoichiometric or non-stoichiometric amounts of a solvent, and may beformed during the process of crystallization with pharmaceuticallyacceptable solvents such as water, ethanol, and the like. Hydrates areformed when the solvent is water, or alcoholates are formed when thesolvent is alcohol. Solvates of compounds described herein can beconveniently prepared or formed during the processes described herein.In addition, the compounds provided herein can exist in unsolvated aswell as solvated forms. In general, the solvated forms are consideredequivalent to the unsolvated forms for the purposes of the compounds andmethods provided herein.

It should be understood that a reference to a salt includes the solventaddition forms or crystal forms thereof, particularly solvates orpolymorphs. Solvates contain either stoichiometric or non-stoichiometricamounts of a solvent, and are often formed during the process ofcrystallization with pharmaceutically acceptable solvents such as water,ethanol, and the like. Hydrates are formed when the solvent is water, oralcoholates are formed when the solvent is alcohol. Polymorphs includethe different crystal packing arrangements of the same elementalcomposition of a compound. Polymorphs usually have different X-raydiffraction patterns, infrared spectra, melting points, density,hardness, crystal shape, optical and electrical properties, stability,and solubility. Various factors such as the recrystallization solvent,rate of crystallization, and storage temperature may cause a singlecrystal form to dominate.

Compounds described herein may be in various forms, including but notlimited to, amorphous forms, milled forms and nano-particulate forms. Inaddition, compounds described herein include crystalline forms, alsoknown as polymorphs. Polymorphs include the different crystal packingarrangements of the same elemental composition of a compound. Polymorphsusually have different X-ray diffraction patterns, infrared spectra,melting points, density, hardness, crystal shape, optical and electricalproperties, stability, and solubility. Various factors such as therecrystallization solvent, rate of crystallization, and storagetemperature may cause a single crystal form to dominate.

The screening and characterization of the pharmaceutically acceptablesalts, polymorphs and/or solvates may be accomplished using a variety oftechniques including, but not limited to, thermal analysis, x-raydiffraction, spectroscopy, vapor sorption, and microscopy. Thermalanalysis methods address thermo chemical degradation or thermo physicalprocesses including, but not limited to, polymorphic transitions, andsuch methods are used to analyze the relationships between polymorphicforms, determine weight loss, to find the glass transition temperature,or for excipient compatibility studies. Such methods include, but arenot limited to, Differential scanning calorimetry (DSC), ModulatedDifferential Scanning Calorimetry (MDCS), Thermogravimetric analysis(TGA), and Thermogravi-metric and Infrared analysis (TG/IR). X-raydiffraction methods include, but are not limited to, single crystal andpowder diffractometers and synchrotron sources. The variousspectroscopic techniques used include, but are not limited to, Raman,FTIR, UVIS, and NMR (liquid and solid state). The various microscopytechniques include, but are not limited to, polarized light microscopy,Scanning Electron Microscopy (SEM) with Energy Dispersive X-Ray Analysis(EDX), Environmental Scanning Electron Microscopy with EDX (in gas orwater vapor atmosphere), IR microscopy, and Raman microscopy.

Throughout the specification, groups and substituents thereof can bechosen by one skilled in the field to provide stable moieties andcompounds.

Pharmaceutical Composition/Formulation

Pharmaceutical compositions may be formulated in a conventional mannerusing one or more physiologically acceptable carriers includingexcipients and auxiliaries which facilitate processing of the activecompounds into preparations which can be used pharmaceutically. Properformulation is dependent upon the route of administration chosen. Any ofthe well-known techniques, carriers, and excipients may be used assuitable and as understood in the art. A summary of pharmaceuticalcompositions described herein may be found, for example, in Remington:The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: MackPublishing Company, 1995); Hoover, John E., Remington's PharmaceuticalSciences, Mack Publishing Co., Easton, Pa. 1975; Liberman, H. A. andLachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York,N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems,Seventh Ed. (Lippincott Williams & Wilkins 1999), herein incorporated byreference in their entirety.

A pharmaceutical composition, as used herein, refers to a mixture of acompound described herein, such as, for example, compounds of any ofFormula (I)-(XLIIIc) with other chemical components, such as carriers,stabilizers, diluents, dispersing agents, suspending agents, thickeningagents, and/or excipients. The pharmaceutical composition facilitatesadministration of the compound to an organism. In practicing the methodsof treatment or use provided herein, therapeutically effective amountsof compounds described herein are administered in a pharmaceuticalcomposition to a mammal having a disease, disorder, or condition to betreated. Preferably, the mammal is a human. A therapeutically effectiveamount can vary widely depending on the severity of the disease, the ageand relative health of the subject, the potency of the compound used andother factors. The compounds can be used singly or in combination withone or more therapeutic agents as components of mixtures.

In certain embodiments, compositions may also include one or more pHadjusting agents or buffering agents, including acids such as acetic,boric, citric, lactic, phosphoric and hydrochloric acids; bases such assodium hydroxide, sodium phosphate, sodium borate, sodium citrate,sodium acetate, sodium lactate and tris-hydroxymethylaminomethane; andbuffers such as citrate/dextrose, sodium bicarbonate and ammoniumchloride. Such acids, bases and buffers are included in an amountrequired to maintain pH of the composition in an acceptable range.

In some embodiments, compositions may also include one or more salts inan amount required to bring osmolality of the composition into anacceptable range. Such salts include those having sodium, potassium orammonium cations and chloride, citrate, ascorbate, borate, phosphate,bicarbonate, sulfate, thiosulfate or bisulfite anions; suitable saltsinclude sodium chloride, potassium chloride, sodium thiosulfate, sodiumbisulfite and ammonium sulfate.

The term “pharmaceutical combination” as used herein, means a productthat results from the mixing or combining of more than one activeingredient and includes both fixed and non-fixed combinations of theactive ingredients. The term “fixed combination” means that the activeingredients, e.g. a compound described herein and a co-agent, are bothadministered to a patient simultaneously in the form of a single entityor dosage. The term “non-fixed combination” means that the activeingredients, e.g. a compound described herein and a co-agent, areadministered to a patient as separate entities either simultaneously,concurrently or sequentially with no specific intervening time limits,wherein such administration provides effective levels of the twocompounds in the body of the patient. The latter also applies tococktail therapy, e.g. the administration of three or more activeingredients.

The pharmaceutical compositions described herein can be administered toa subject by multiple administration routes, including but not limitedto, oral, parenteral (e.g., intravenous, subcutaneous, intramuscular),intranasal, buccal, topical, rectal, or transdermal administrationroutes. The pharmaceutical compositions described herein include, butare not limited to, aqueous liquid dispersions, self-emulsifyingdispersions, solid solutions, liposomal dispersions, aerosols, soliddosage forms, powders, immediate release formulations, controlledrelease formulations, fast melt formulations, tablets, capsules, pills,delayed release formulations, extended release formulations, pulsatilerelease formulations, multiparticulate formulations, and mixed immediateand controlled release formulations.

Pharmaceutical compositions including a compound described herein may bemanufactured in a conventional manner, such as, by way of example only,by means of conventional mixing, dissolving, granulating, dragee-making,levigating, emulsifying, encapsulating, entrapping or compressionprocesses.

The pharmaceutical compositions will include at least one compounddescribed herein, such as, for example, a compound of any of Formula(I)-(XLIIIc) as an active ingredient in free-acid or free-base form, orin a pharmaceutically acceptable salt form. In addition, the methods andpharmaceutical compositions described herein include the use ofN-oxides, crystalline forms (also known as polymorphs), as well asactive metabolites of these compounds having the same type of activity.In some situations, compounds may exist as tautomers. All tautomers areincluded within the scope of the compounds presented herein.Additionally, the compounds described herein can exist in unsolvated aswell as solvated forms with pharmaceutically acceptable solvents such aswater, ethanol, and the like. The solvated forms of the compoundspresented herein are also considered to be disclosed herein.

“Antifoaming agents” reduce foaming during processing which can resultin coagulation of aqueous dispersions, bubbles in the finished film, orgenerally impair processing. Exemplary anti-foaming agents includesilicon emulsions or sorbitan sesquoleate.

“Antioxidants” include, for example, butylated hydroxytoluene (BHT),sodium ascorbate, ascorbic acid, sodium metabisulfite and tocopherol. Incertain embodiments, antioxidants enhance chemical stability whererequired.

In certain embodiments, compositions provided herein may also includeone or more preservatives to inhibit microbial activity. Suitablepreservatives include mercury-containing substances such as merfen andthiomersal; stabilized chlorine dioxide; and quaternary ammoniumcompounds such as benzalkonium chloride, cetyltrimethylammonium bromideand cetylpyridinium chloride.

Formulations described herein may benefit from antioxidants, metalchelating agents, thiol containing compounds and other generalstabilizing agents. Examples of such stabilizing agents, include, butare not limited to: (a) about 0.5% to about 2% w/v glycerol, (b) about0.1% to about 1% w/v methionine, (c) about 0.1% to about 2% w/vmonothioglycerol, (d) about 1 mM to about 10 mM EDTA, (e) about 0.01% toabout 2% w/v ascorbic acid, (f) 0.003% to about 0.02% w/v polysorbate80, (g) 0.001% to about 0.05% w/v. polysorbate 20, (h) arginine, (i)heparin, (j) dextran sulfate, (k) cyclodextrins, (1) pentosanpolysulfate and other heparinoids, (m) divalent cations such asmagnesium and zinc; or (n) combinations thereof.

“Binders” impart cohesive qualities and include, e.g., alginic acid andsalts thereof; cellulose derivatives such as carboxymethylcellulose,methylcellulose (e.g., Methocel®), hydroxypropylmethylcellulose,hydroxyethylcellulose, hydroxypropylcellulose (e.g., Klucel®),ethylcellulose (e.g., Ethocel®), and microcrystalline cellulose (e.g.,Avicel®); microcrystalline dextrose; amylose; magnesium aluminumsilicate; polysaccharide acids; bentonites; gelatin;polyvinylpyrrolidone/vinyl acetate copolymer; crosspovidone; povidone;starch; pregelatinized starch; tragacanth, dextrin, a sugar, such assucrose (e.g., Dipac®), glucose, dextrose, molasses, mannitol, sorbitol,xylitol (e.g., Xylitab®), and lactose; a natural or synthetic gum suchas acacia, tragacanth, ghatti gum, mucilage of isapol husks,polyvinylpyrrolidone (e.g., Polyvidone® CL, Kollidon® CL, Polyplasdone®XL-10), larch arabogalactan, Veegum®, polyethylene glycol, waxes, sodiumalginate, and the like.

A “carrier” or “carrier materials” include any commonly used excipientsin pharmaceutics and should be selected on the basis of compatibilitywith compounds disclosed herein, such as, compounds of any of Formula(I)-(XLIIIc) and the release profile properties of the desired dosageform. Exemplary carrier materials include, e.g., binders, suspendingagents, disintegration agents, filling agents, surfactants,solubilizers, stabilizers, lubricants, wetting agents, diluents, and thelike. “Pharmaceutically compatible carrier materials” may include, butare not limited to, acacia, gelatin, colloidal silicon dioxide, calciumglycerophosphate, calcium lactate, maltodextrin, glycerine, magnesiumsilicate, polyvinylpyrrollidone (PVP), cholesterol, cholesterol esters,sodium caseinate, soy lecithin, taurocholic acid, phosphotidylcholine,sodium chloride, tricalcium phosphate, dipotassium phosphate, celluloseand cellulose conjugates, sugars sodium stearoyl lactylate, carrageenan,monoglyceride, diglyceride, pregelatinized starch, and the like. See,e.g., Remington: The Science and Practice of Pharmacy, Nineteenth Ed(Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E.,Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa.1975; Liberman, H. A. and Lachman, L., Eds., Pharmaceutical DosageForms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical DosageForms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams &Wilkins 1999).

“Dispersing agents,” and/or “viscosity modulating agents” includematerials that control the diffusion and homogeneity of a drug throughliquid media or a granulation method or blend method. In someembodiments, these agents also facilitate the effectiveness of a coatingor eroding matrix. Exemplary diffusion facilitators/dispersing agentsinclude, e.g., hydrophilic polymers, electrolytes, Tween® 60 or 80, PEG,polyvinylpyrrolidone (PVP; commercially known as Plasdone®), and thecarbohydrate-based dispersing agents such as, for example, hydroxypropylcelluloses (e.g., HPC, HPC-SL, and HPC-L), hydroxypropylmethylcelluloses (e.g., HPMC K100, HPMC K4M, HPMC K15M, and HPMC K100M),carboxymethylcellulose sodium, methylcellulose, hydroxyethylcellulose,hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate,hydroxypropylmethylcellulose acetate stearate (HPMCAS), noncrystallinecellulose, magnesium aluminum silicate, triethanolamine, polyvinylalcohol (PVA), vinyl pyrrolidone/vinyl acetate copolymer (S630),4-(1,1,3,3-tetramethylbutyl)-phenol polymer with ethylene oxide andformaldehyde (also known as tyloxapol), poloxamers (e.g., PluronicsF68®, F88®, and F108®, which are block copolymers of ethylene oxide andpropylene oxide); and poloxamines (e.g., Tetronic 908®, also known asPoloxamine 908®, which is a tetrafunctional block copolymer derived fromsequential addition of propylene oxide and ethylene oxide toethylenediamine (BASF Corporation, Parsippany, N.J.)),polyvinylpyrrolidone K12, polyvinylpyrrolidone K17, polyvinylpyrrolidoneK25, or polyvinylpyrrolidone K30, polyvinylpyrrolidone/vinyl acetatecopolymer (S-630), polyethylene glycol, e.g., the polyethylene glycolcan have a molecular weight of about 300 to about 6000, or about 3350 toabout 4000, or about 7000 to about 5400, sodium carboxymethylcellulose,methylcellulose, polysorbate-80, sodium alginate, gums, such as, e.g.,gum tragacanth and gum acacia, guar gum, xanthans, including xanthangum, sugars, cellulosics, such as, e.g., sodium carboxymethylcellulose,methylcellulose, sodium carboxymethylcellulose, polysorbate-80, sodiumalginate, polyethoxylated sorbitan monolaurate, polyethoxylated sorbitanmonolaurate, povidone, carbomers, polyvinyl alcohol (PVA), alginates,chitosans and combinations thereof. Plasticizcers such as cellulose ortriethyl cellulose can also be used as dispersing agents. Dispersingagents particularly useful in liposomal dispersions and self-emulsifyingdispersions are dimyristoyl phosphatidyl choline, natural phosphatidylcholine from eggs, natural phosphatidyl glycerol from eggs, cholesteroland isopropyl myristate.

Combinations of one or more erosion facilitator with one or morediffusion facilitator can also be used in the present compositions.

The term “diluent” refers to chemical compounds that are used to dilutethe compound of interest prior to delivery. Diluents can also be used tostabilize compounds because they can provide a more stable environment.Salts dissolved in buffered solutions (which also can provide pH controlor maintenance) are utilized as diluents in the art, including, but notlimited to a phosphate buffered saline solution. In certain embodiments,diluents increase bulk of the composition to facilitate compression orcreate sufficient bulk for homogenous blend for capsule filling. Suchcompounds include e.g., lactose, starch, mannitol, sorbitol, dextrose,microcrystalline cellulose such as Avicel®; dibasic calcium phosphate,dicalcium phosphate dihydrate; tricalcium phosphate, calcium phosphate;anhydrous lactose, spray-dried lactose; pregelatinized starch,compressible sugar, such as Di-Pac® (Amstar); mannitol,hydroxypropylmethylcellulose, hydroxypropylmethylcellulose acetatestearate, sucrose-based diluents, confectioner's sugar; monobasiccalcium sulfate monohydrate, calcium sulfate dihydrate; calcium lactatetrihydrate, dextrates; hydrolyzed cereal solids, amylose; powderedcellulose, calcium carbonate; glycine, kaolin; mannitol, sodiumchloride; inositol, bentonite, and the like.

The term “disintegrate” includes both the dissolution and dispersion ofthe dosage form when contacted with gastrointestinal fluid.“Disintegration agents or disintegrants” facilitate the breakup ordisintegration of a substance. Examples of disintegration agents includea starch, e.g., a natural starch such as corn starch or potato starch, apregelatinized starch such as National 1551 or Amijel®, or sodium starchglycolate such as Promogel® or Explotab®, a cellulose such as a woodproduct, methylcrystalline cellulose, e.g., Avicel®, Avicel® PH1101,Avicel® PH102, Avicel® PH105, Elcema® P100, Emcocel®, Vivacel®, MingTia®, and Solka-Floc®, methylcellulose, croscarmellose, or across-linked cellulose, such as cross-linked sodiumcarboxymethylcellulose (Ac-Di-Sol®), cross-linkedcarboxymethylcellulose, or cross-linked croscarmellose, a cross-linkedstarch such as sodium starch glycolate, a cross-linked polymer such ascrosspovidone, a cross-linked polyvinylpyrrolidone, alginate such asalginic acid or a salt of alginic acid such as sodium alginate, a claysuch as Veegum® HV (magnesium aluminum silicate), a gum such as agar,guar, locust bean, Karaya, pectin, or tragacanth, sodium starchglycolate, bentonite, a natural sponge, a surfactant, a resin such as acation-exchange resin, citrus pulp, sodium lauryl sulfate, sodium laurylsulfate in combination starch, and the like.

“Drug absorption” or “absorption” typically refers to the process ofmovement of drug from site of administration of a drug across a barrierinto a blood vessel or the site of action, e.g., a drug moving from thegastrointestinal tract into the portal vein or lymphatic system.

An “enteric coating” is a substance that remains substantially intact inthe stomach but dissolves and releases the drug in the small intestineor colon. Generally, the enteric coating comprises a polymeric materialthat prevents release in the low pH environment of the stomach but thationizes at a higher pH, typically a pH of 6 to 7, and thus dissolvessufficiently in the small intestine or colon to release the active agenttherein.

“Erosion facilitators” include materials that control the erosion of aparticular material in gastrointestinal fluid. Erosion facilitators aregenerally known to those of ordinary skill in the art. Exemplary erosionfacilitators include, e.g., hydrophilic polymers, electrolytes,proteins, peptides, and amino acids.

“Filling agents” include compounds such as lactose, calcium carbonate,calcium phosphate, dibasic calcium phosphate, calcium sulfate,microcrystalline cellulose, cellulose powder, dextrose, dextrates,dextran, starches, pregelatinized starch, sucrose, xylitol, lactitol,mannitol, sorbitol, sodium chloride, polyethylene glycol, and the like.

“Flavoring agents” and/or “sweeteners” useful in the formulationsdescribed herein, include, e.g., acacia syrup, acesulfame K, alitame,anise, apple, aspartame, banana, Bavarian cream, berry, black currant,butterscotch, calcium citrate, camphor, caramel, cherry, cherry cream,chocolate, cinnamon, bubble gum, citrus, citrus punch, citrus cream,cotton candy, cocoa, cola, cool cherry, cool citrus, cyclamate,cylamate, dextrose, eucalyptus, eugenol, fructose, fruit punch, ginger,glycyrrhetinate, glycyrrhiza (licorice) syrup, grape, grapefruit, honey,isomalt, lemon, lime, lemon cream, monoammonium glyrrhizinate(MagnaSweet®), maltol, mannitol, maple, marshmallow, menthol, mintcream, mixed berry, neohesperidine DC, neotame, orange, pear, peach,peppermint, peppermint cream, Prosweet® Powder, raspberry, root beer,rum, saccharin, safrole, sorbitol, spearmint, spearmint cream,strawberry, strawberry cream, stevia, sucralose, sucrose, sodiumsaccharin, saccharin, aspartame, acesulfame potassium, mannitol, talin,sylitol, sucralose, sorbitol, Swiss cream, tagatose, tangerine,thaumatin, tutti fruitti, vanilla, walnut, watermelon, wild cherry,wintergreen, xylitol, or any combination of these flavoring ingredients,e.g., anise-menthol, cherry-anise, cinnamon-orange, cherry-cinnamon,chocolate-mint, honey-lemon, lemon-lime, lemon-mint, menthol-eucalyptus,orange-cream, vanilla-mint, and mixtures thereof.

“Lubricants” and “glidants” are compounds that prevent, reduce orinhibit adhesion or friction of materials. Exemplary lubricants include,e.g., stearic acid, calcium hydroxide, talc, sodium stearyl fumerate, ahydrocarbon such as mineral oil, or hydrogenated vegetable oil such ashydrogenated soybean oil (Sterotex®), higher fatty acids and theiralkali-metal and alkaline earth metal salts, such as aluminum, calcium,magnesium, zinc, stearic acid, sodium stearates, glycerol, talc, waxes,Stearowet®, boric acid, sodium benzoate, sodium acetate, sodiumchloride, leucine, a polyethylene glycol (e.g., PEG-4000) or amethoxypolyethylene glycol such as Carbowax™, sodium oleate, sodiumbenzoate, glyceryl behenate, polyethylene glycol, magnesium or sodiumlauryl sulfate, colloidal silica such as Syloid™, Cab-O-Sil®, a starchsuch as corn starch, silicone oil, a surfactant, and the like.

A “measurable serum concentration” or “measurable plasma concentration”describes the blood serum or blood plasma concentration, typicallymeasured in mg, μg, or ng of therapeutic agent per ml, dl, or 1 of bloodserum, absorbed into the bloodstream after administration. As usedherein, measurable plasma concentrations are typically measured in ng/mlor μg/ml.

“Pharmacodynamics” refers to the factors which determine the biologicresponse observed relative to the concentration of drug at a site ofaction.

“Pharmacokinetics” refers to the factors which determine the attainmentand maintenance of the appropriate concentration of drug at a site ofaction.

“Plasticizers” are compounds used to soften the microencapsulationmaterial or film coatings to make them less brittle. Suitableplasticizers include, e.g., polyethylene glycols such as PEG 300, PEG400, PEG 600, PEG 1450, PEG 3350, and PEG 800, stearic acid, propyleneglycol, oleic acid, triethyl cellulose and triacetin. In someembodiments, plasticizers can also function as dispersing agents orwetting agents.

“Solubilizers” include compounds such as triacetin, triethylcitrate,ethyl oleate, ethyl caprylate, sodium lauryl sulfate, sodium doccusate,vitamin E TPGS, dimethylacetamide, N-methylpyrrolidone,N-hydroxyethylpyrrolidone, polyvinylpyrrolidone, hydroxypropylmethylcellulose, hydroxypropyl cyclodextrins, ethanol, n-butanol, isopropylalcohol, cholesterol, bile salts, polyethylene glycol 200-600,glycofurol, transcutol, propylene glycol, and dimethyl isosorbide andthe like.

“Stabilizers” include compounds such as any antioxidation agents,buffers, acids, preservatives and the like.

“Steady state,” as used herein, is when the amount of drug administeredis equal to the amount of drug eliminated within one dosing intervalresulting in a plateau or constant plasma drug exposure.

“Suspending agents” include compounds such as polyvinylpyrrolidone,e.g., polyvinylpyrrolidone K12, polyvinylpyrrolidone K17,polyvinylpyrrolidone K25, or polyvinylpyrrolidone K30, vinylpyrrolidone/vinyl acetate copolymer (S630), polyethylene glycol, e.g.,the polyethylene glycol can have a molecular weight of about 300 toabout 6000, or about 3350 to about 4000, or about 7000 to about 5400,sodium carboxymethylcellulose, methylcellulose,hydroxypropylmethylcellulose, hydroxymethylcellulose acetate stearate,polysorbate-80, hydroxyethylcellulose, sodium alginate, gums, such as,e.g., gum tragacanth and gum acacia, guar gum, xanthans, includingxanthan gum, sugars, cellulosics, such as, e.g., sodiumcarboxymethylcellulose, methylcellulose, sodium carboxymethylcellulose,hydroxypropylmethylcellulose, hydroxyethylcellulose, polysorbate-80,sodium alginate, polyethoxylated sorbitan monolaurate, polyethoxylatedsorbitan monolaurate, povidone and the like.

“Surfactants” include compounds such as sodium lauryl sulfate, sodiumdocusate, Tween 60 or 80, triacetin, vitamin E TPGS, sorbitanmonooleate, polyoxyethylene sorbitan monooleate, polysorbates,polaxomers, bile salts, glyceryl monostearate, copolymers of ethyleneoxide and propylene oxide, e.g., Pluronic® (BASF), and the like. Someother surfactants include polyoxyethylene fatty acid glycerides andvegetable oils, e.g., polyoxyethylene (60) hydrogenated castor oil; andpolyoxyethylene alkylethers and alkylphenyl ethers, e.g., octoxynol 10,octoxynol 40. In some embodiments, surfactants may be included toenhance physical stability or for other purposes.

“Viscosity enhancing agents” include, e.g., methyl cellulose, xanthangum, carboxymethyl cellulose, hydroxypropyl cellulose,hydroxypropylmethyl cellulose, hydroxypropylmethyl cellulose acetatestearate, hydroxypropylmethyl cellulose phthalate, carbomer, polyvinylalcohol, alginates, acacia, chitosans and combinations thereof.

“Wetting agents” include compounds such as oleic acid, glycerylmonostearate, sorbitan monooleate, sorbitan monolaurate, triethanolamineoleate, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitanmonolaurate, sodium docusate, sodium oleate, sodium lauryl sulfate,sodium doccusate, triacetin, Tween 80, vitamin E TPGS, ammonium saltsand the like.

Dosage Forms

The compositions described herein can be formulated for administrationto a subject via any conventional means including, but not limited to,oral, parenteral (e.g., intravenous, subcutaneous, or intramuscular),buccal, intranasal, rectal or transdermal administration routes. As usedherein, the term “subject” is used to mean an animal, preferably amammal, including a human or non-human. The terms patient and subjectmay be used interchangeably.

Moreover, the pharmaceutical compositions described herein, whichinclude a compound of any of Formula (I)-(XLIIIc) can be formulated intoany suitable dosage form, including but not limited to, aqueous oraldispersions, liquids, gels, syrups, elixirs, slurries, suspensions andthe like, for oral ingestion by a patient to be treated, solid oraldosage forms, aerosols, controlled release formulations, fast meltformulations, effervescent formulations, lyophilized formulations,tablets, powders, pills, dragees, capsules, delayed releaseformulations, extended release formulations, pulsatile releaseformulations, multiparticulate formulations, and mixed immediate releaseand controlled release formulations.

Pharmaceutical preparations for oral use can be obtained by mixing oneor more solid excipient with one or more of the compounds describedherein, optionally grinding the resulting mixture, and processing themixture of granules, after adding suitable auxiliaries, if desired, toobtain tablets or dragee cores. Suitable excipients include, forexample, fillers such as sugars, including lactose, sucrose, mannitol,or sorbitol; cellulose preparations such as, for example, maize starch,wheat starch, rice starch, potato starch, gelatin, gum tragacanth,methylcellulose, microcrystalline cellulose,hydroxypropylmethylcellulose, sodium carboxymethylcellulose; or otherssuch as: polyvinylpyrrolidone (PVP or povidone) or calcium phosphate. Ifdesired, disintegrating agents may be added, such as the cross-linkedcroscarmellose sodium, polyvinylpyrrolidone, agar, or alginic acid or asalt thereof such as sodium alginate.

Dragee cores are provided with suitable coatings. For this purpose,concentrated sugar solutions may be used, which may optionally containgum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethyleneglycol, and/or titanium dioxide, lacquer solutions, and suitable organicsolvents or solvent mixtures. Dyestuffs or pigments may be added to thetablets or dragee coatings for identification or to characterizedifferent combinations of active compound doses.

Pharmaceutical preparations which can be used orally include push-fitcapsules made of gelatin, as well as soft, sealed capsules made ofgelatin and a plasticizer, such as glycerol or sorbitol. The push-fitcapsules can contain the active ingredients in admixture with fillersuch as lactose, binders such as starches, and/or lubricants such astalc or magnesium stearate and, optionally, stabilizers. In softcapsules, the active compounds may be dissolved or suspended in suitableliquids, such as fatty oils, liquid paraffin, or liquid polyethyleneglycols. In addition, stabilizers may be added. All formulations fororal administration should be in dosages suitable for suchadministration.

In some embodiments, the solid dosage forms disclosed herein may be inthe form of a tablet, (including a suspension tablet, a fast-melttablet, a bite-disintegration tablet, a rapid-disintegration tablet, aneffervescent tablet, or a caplet), a pill, a powder (including a sterilepackaged powder, a dispensable powder, or an effervescent powder) acapsule (including both soft or hard capsules, e.g., capsules made fromanimal-derived gelatin or plant-derived HPMC, or “sprinkle capsules”),solid dispersion, solid solution, bioerodible dosage form, controlledrelease formulations, pulsatile release dosage forms, multiparticulatedosage forms, pellets, granules, or an aerosol. In some embodiments, thepharmaceutical composition is in the form of a powder. In someembodiments, the pharmaceutical composition is in the form of a tablet,including but not limited to, a fast-melt tablet. Additionally,pharmaceutical compositions described herein may be administered as asingle capsule or in multiple capsule dosage form. In some embodiments,the pharmaceutical composition is administered in two, or three, orfour, capsules or tablets.

In some embodiments, solid dosage forms, e.g., tablets, effervescenttablets, and capsules, are prepared by mixing particles of a compound ofany of Formula (I)-(XLIIIc) with one or more pharmaceutical excipientsto form a bulk blend composition. When referring to these bulk blendcompositions as homogeneous, it is meant that the particles of thecompound of any of Formula (I)-(XLIIIc) are dispersed evenly throughoutthe composition so that the composition may be readily subdivided intoequally effective unit dosage forms, such as tablets, pills, andcapsules. The individual unit dosages may also include film coatings,which disintegrate upon oral ingestion or upon contact with diluent.These formulations can be manufactured by conventional pharmacologicaltechniques.

Conventional pharmacological techniques include, e.g., one or acombination of methods: (1) dry mixing, (2) direct compression, (3)milling, (4) dry or non-aqueous granulation, (5) wet granulation, or (6)fusion. See, e.g., Lachman et al., The Theory and Practice of IndustrialPharmacy (1986). Other methods include, e.g., spray drying, pan coating,melt granulation, granulation, fluidized bed spray drying or coating(e.g., wurster coating), tangential coating, top spraying, tableting,extruding and the like.

The pharmaceutical solid dosage forms described herein can include acompound described herein and one or more pharmaceutically acceptableadditives such as a compatible carrier, binder, filling agent,suspending agent, flavoring agent, sweetening agent, disintegratingagent, dispersing agent, surfactant, lubricant, colorant, diluent,solubilizer, moistening agent, plasticizer, stabilizer, penetrationenhancer, wetting agent, anti-foaming agent, antioxidant, preservative,or one or more combination thereof. In some embodiments, using standardcoating procedures, such as those described in Remington'sPharmaceutical Sciences, 20th Edition (2000), a film coating is providedaround the formulation of the compound of any of Formula (I)-(XVII). Insome embodiments, some or all of the particles of the compound of any ofFormula (I)-(XLIIIc) are coated. In some embodiments, some or all of theparticles of the compound of any of Formula (I)-(XVII), aremicroencapsulated. In still some embodiments, the particles of thecompound of any of Formula (I)-(XLIIIc) are not microencapsulated andare uncoated.

Suitable carriers for use in the solid dosage forms described hereininclude, but are not limited to, acacia, gelatin, colloidal silicondioxide, calcium glycerophosphate, calcium lactate, maltodextrin,glycerine, magnesium silicate, sodium caseinate, soy lecithin, sodiumchloride, tricalcium phosphate, dipotassium phosphate, sodium stearoyllactylate, carrageenan, monoglyceride, diglyceride, pregelatinizedstarch, hydroxypropylmethylcellulose, hydroxypropylmethylcelluloseacetate stearate, sucrose, microcrystalline cellulose, lactose, mannitoland the like.

Suitable filling agents for use in the solid dosage forms describedherein include, but are not limited to, lactose, calcium carbonate,calcium phosphate, dibasic calcium phosphate, calcium sulfate,microcrystalline cellulose, cellulose powder, dextrose, dextrates,dextran, starches, pregelatinized starch, hydroxypropylmethycellulose(HPMC), hydroxypropylmethycellulose phthalate,hydroxypropylmethylcellulose acetate stearate (HPMCAS), sucrose,xylitol, lactitol, mannitol, sorbitol, sodium chloride, polyethyleneglycol, and the like.

In order to release the compound of any of Formula (I)-(XLIIIc) from asolid dosage form matrix as efficiently as possible, disintegrants areoften used in the formulation, especially when the dosage forms arecompressed with binder. Disintegrants help rupturing the dosage formmatrix by swelling or capillary action when moisture is absorbed intothe dosage form. Suitable disintegrants for use in the solid dosageforms described herein include, but are not limited to, natural starchsuch as corn starch or potato starch, a pregelatinized starch such asNational 1551 or Amijel®, or sodium starch glycolate such as Promogel®or Explotab®, a cellulose such as a wood product, methylcrystallinecellulose, e.g., Avicel®, Avicel® PH101, Avicel® PH102, Avicel® PH105,Elcema® P100, Emcocel®, Vivacel®, Ming Tia®, and Solka-Floc®,methylcellulose, croscarmellose, or a cross-linked cellulose, such ascross-linked sodium carboxymethylcellulose (Ac-Di-Sol®), cross-linkedcarboxymethylcellulose, or cross-linked croscarmellose, a cross-linkedstarch such as sodium starch glycolate, a cross-linked polymer such ascrospovidone, a cross-linked polyvinylpyrrolidone, alginate such asalginic acid or a salt of alginic acid such as sodium alginate, a claysuch as Veegum® HV (magnesium aluminum silicate), a gum such as agar,guar, locust bean, Karaya, pectin, or tragacanth, sodium starchglycolate, bentonite, a natural sponge, a surfactant, a resin such as acation-exchange resin, citrus pulp, sodium lauryl sulfate, sodium laurylsulfate in combination starch, and the like.

Binders impart cohesiveness to solid oral dosage form formulations: forpowder filled capsule formulation, they aid in plug formation that canbe filled into soft or hard shell capsules and for tablet formulation,they ensure the tablet remaining intact after compression and helpassure blend uniformity prior to a compression or fill step. Materialssuitable for use as binders in the solid dosage forms described hereininclude, but are not limited to, carboxymethylcellulose, methylcellulose(e.g., Methocel®), hydroxypropylmethylcellulose (e.g. Hypromellose USPPharmacoat-603, hydroxypropylmethylcellulose acetate stearate (AgoateHS-LF and HS), hydroxyethylcellulose, hydroxypropylcellulose (e.g.,Klucel®), ethylcellulose (e.g., Ethocel®), and microcrystallinecellulose (e.g., Avicel®), microcrystalline dextrose, amylose, magnesiumaluminum silicate, polysaccharide acids, bentonites, gelatin,polyvinylpyrrolidone/vinyl acetate copolymer, crospovidone, povidone,starch, pregelatinized starch, tragacanth, dextrin, a sugar, such assucrose (e.g., Dipac®), glucose, dextrose, molasses, mannitol, sorbitol,xylitol (e.g., Xylitab®), lactose, a natural or synthetic gum such asacacia, tragacanth, ghatti gum, mucilage of isapol husks, starch,polyvinylpyrrolidone (e.g., Povidone® CL, Kollidon® CL, Polyplasdone®XL-10, and Povidone® K-12), larch arabogalactan, Veegum®, polyethyleneglycol, waxes, sodium alginate, and the like.

In general, binder levels of 20-70% are used in powder-filled gelatincapsule formulations. Binder usage level in tablet formulations varieswhether direct compression, wet granulation, roller compaction, or usageof other excipients such as fillers which itself can act as moderatebinder. Formulators skilled in art can determine the binder level forthe formulations, but binder usage level of up to 70% in tabletformulations is common.

Suitable lubricants or glidants for use in the solid dosage formsdescribed herein include, but are not limited to, stearic acid, calciumhydroxide, talc, corn starch, sodium stearyl fumerate, alkali-metal andalkaline earth metal salts, such as aluminum, calcium, magnesium, zinc,stearic acid, sodium stearates, magnesium stearate, zinc stearate,waxes, Stearowet®, boric acid, sodium benzoate, sodium acetate, sodiumchloride, leucine, a polyethylene glycol or a methoxypolyethylene glycolsuch as Carbowax™, PEG 4000, PEG 5000, PEG 6000, propylene glycol,sodium oleate, glyceryl behenate, glyceryl palmitostearate, glycerylbenzoate, magnesium or sodium lauryl sulfate, and the like.

Suitable diluents for use in the solid dosage forms described hereininclude, but are not limited to, sugars (including lactose, sucrose, anddextrose), polysaccharides (including dextrates and maltodextrin),polyols (including mannitol, xylitol, and sorbitol), cyclodextrins andthe like.

The term “non water-soluble diluent” represents compounds typically usedin the formulation of pharmaceuticals, such as calcium phosphate,calcium sulfate, starches, modified starches and microcrystallinecellulose, and microcellulose (e.g., having a density of about 0.45g/cm³, e.g. Avicel, powdered cellulose), and talc.

Suitable wetting agents for use in the solid dosage forms describedherein include, for example, oleic acid, glyceryl monostearate, sorbitanmonooleate, sorbitan monolaurate, triethanolamine oleate,polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitanmonolaurate, quaternary ammonium compounds (e.g., Polyquat 10®), sodiumoleate, sodium lauryl sulfate, magnesium stearate, sodium docusate,triacetin, vitamin E TPGS and the like.

Suitable surfactants for use in the solid dosage forms described hereininclude, for example, sodium lauryl sulfate, sorbitan monooleate,polyoxyethylene sorbitan monooleate, polysorbates, polaxomers, bilesalts, glyceryl monostearate, copolymers of ethylene oxide and propyleneoxide, e.g., Pluronic® (BASF), and the like.

Suitable suspending agents for use in the solid dosage forms describedhere include, but are not limited to, polyvinylpyrrolidone, e.g.,polyvinylpyrrolidone K12, polyvinylpyrrolidone K17, polyvinylpyrrolidoneK25, or polyvinylpyrrolidone K30, polyethylene glycol, e.g., thepolyethylene glycol can have a molecular weight of about 300 to about6000, or about 3350 to about 4000, or about 7000 to about 5400, vinylpyrrolidone/vinyl acetate copolymer (S630), sodiumcarboxymethylcellulose, methylcellulose, hydroxy-propylmethylcellulose,polysorbate-80, hydroxyethylcellulose, sodium alginate, gums, such as,e.g., gum tragacanth and gum acacia, guar gum, xanthans, includingxanthan gum, sugars, cellulosics, such as, e.g., sodiumcarboxymethylcellulose, methylcellulose, sodium carboxymethylcellulose,hydroxypropylmethylcellulose, hydroxyethylcellulose, polysorbate-80,sodium alginate, polyethoxylated sorbitan monolaurate, polyethoxylatedsorbitan monolaurate, povidone and the like.

Suitable antioxidants for use in the solid dosage forms described hereininclude, for example, e.g., butylated hydroxytoluene (BHT), sodiumascorbate, and tocopherol.

It should be appreciated that there is considerable overlap betweenadditives used in the solid dosage forms described herein. Thus, theabove-listed additives should be taken as merely exemplary, and notlimiting, of the types of additives that can be included in solid dosageforms described herein. The amounts of such additives can be readilydetermined by one skilled in the art, according to the particularproperties desired.

In some embodiments, one or more layers of the pharmaceuticalcomposition are plasticized. Illustratively, a plasticizer is generallya high boiling point solid or liquid. Suitable plasticizers can be addedfrom about 0.01% to about 50% by weight (w/w) of the coatingcomposition. Plasticizers include, but are not limited to, diethylphthalate, citrate esters, polyethylene glycol, glycerol, acetylatedglycerides, triacetin, polypropylene glycol, polyethylene glycol,triethyl citrate, dibutyl sebacate, stearic acid, stearol, stearate, andcastor oil.

Compressed tablets are solid dosage forms prepared by compacting thebulk blend of the formulations described above. In various embodiments,compressed tablets which are designed to dissolve in the mouth willinclude one or more flavoring agents. In some embodiments, thecompressed tablets will include a film surrounding the final compressedtablet. In some embodiments, the film coating can provide a delayedrelease of the compound of any of Formula (I)-(XLIIIc) from theformulation. In some embodiments, the film coating aids in patientcompliance (e.g., Opadry® coatings or sugar coating). Film coatingsincluding Opadry® typically range from about 1% to about 3% of thetablet weight. In some embodiments, the compressed tablets include oneor more excipients.

A capsule may be prepared, for example, by placing the bulk blend of theformulation of the compound of any of Formula (I)-(XVII), describedabove, inside of a capsule. In some embodiments, the formulations(non-aqueous suspensions and solutions) are placed in a soft gelatincapsule. In some embodiments, the formulations are placed in standardgelatin capsules or non-gelatin capsules such as capsules comprisingHPMC. In some embodiments, the formulation is placed in a sprinklecapsule, wherein the capsule may be swallowed whole or the capsule maybe opened and the contents sprinkled on food prior to eating. In someembodiments, the therapeutic dose is split into multiple (e.g., two,three, or four) capsules. In some embodiments, the entire dose of theformulation is delivered in a capsule form.

In various embodiments, the particles of the compound of any of Formula(I)-(XLIIIc) and one or more excipients are dry blended and compressedinto a mass, such as a tablet, having a hardness sufficient to provide apharmaceutical composition that substantially disintegrates within lessthan about 30 minutes, less than about 35 minutes, less than about 40minutes, less than about 45 minutes, less than about 50 minutes, lessthan about 55 minutes, or less than about 60 minutes, after oraladministration, thereby releasing the formulation into thegastrointestinal fluid.

In some embodiments, dosage forms may include microencapsulatedformulations. In some embodiments, one or more other compatiblematerials are present in the microencapsulation material. Exemplarymaterials include, but are not limited to, pH modifiers, erosionfacilitators, anti-foaming agents, antioxidants, flavoring agents, andcarrier materials such as binders, suspending agents, disintegrationagents, filling agents, surfactants, solubilizers, stabilizers,lubricants, wetting agents, and diluents.

Materials useful for the microencapsulation described herein includematerials compatible with compounds of any of Formula (I)-(XLIIIc) whichsufficiently isolate the compound of any of Formula (I)-(XLIIIc) fromother non-compatible excipients. Materials compatible with compounds ofany of Formula (I)-(XLIIIc) are those that delay the release of thecompounds of any of Formula (I)-(XVII), in vivo.

Exemplary microencapsulation materials useful for delaying the releaseof the formulations including compounds described herein, include, butare not limited to, hydroxypropyl cellulose ethers (HPC) such as Klucel®or Nisso HPC, low-substituted hydroxypropyl cellulose ethers (L-HPC),hydroxypropyl methyl cellulose ethers (HPMC) such as Seppifilm-LC,Pharmacoat®, Metolose SR, Methocel®-E, Opadry YS, PrimaFlo, BenecelMP824, and Benecel MP843, methylcellulose polymers such as Methocel®-A,hydroxypropylmethylcellulose acetate stearate Aqoat (HF-LS, HF-LG,HF-MS) and Metolose®, Ethylcelluloses (EC) and mixtures thereof such asE461, Ethocel®, Aqualon®-EC, Surelease®, Polyvinyl alcohol (PVA) such asOpadry AMB, hydroxyethylcelluloses such as Natrosol®,carboxymethylcelluloses and salts of carboxymethylcelluloses (CMC) suchas Aqualon®-CMC, polyvinyl alcohol and polyethylene glycol co-polymerssuch as Kollicoat IR®, monoglycerides (Myverol), triglycerides (KLX),polyethylene glycols, modified food starch, acrylic polymers andmixtures of acrylic polymers with cellulose ethers such as Eudragit®EPO, Eudragit® L30D-55, Eudragit® FS 30D Eudragit® L100-55, Eudragit®L100, Eudragit® S100, Eudragit® RD100, Eudragit® E100, Eudragit® L12.5,Eudragit® S12.5, Eudragit® NE30D, and Eudragit® NE 40D, celluloseacetate phthalate, sepifilms such as mixtures of HPMC and stearic acid,cyclodextrins, and mixtures of these materials.

In some embodiments, plasticizers such as polyethylene glycols, e.g.,PEG 300, PEG 400, PEG 600, PEG 1450, PEG 3350, and PEG 800, stearicacid, propylene glycol, oleic acid, and triacetin are incorporated intothe microencapsulation material. In some embodiments, themicroencapsulating material useful for delaying the release of thepharmaceutical compositions is from the USP or the National Formulary(NF). In some embodiments, the microencapsulation material is Klucel. Insome embodiments, the microencapsulation material is methocel.

Microencapsulated compounds of any of Formula (I)-(XLIIIc) may beformulated by methods known by one of ordinary skill in the art. Suchknown methods include, e.g., spray drying processes, spinningdisk-solvent processes, hot melt processes, spray chilling methods,fluidized bed, electrostatic deposition, centrifugal extrusion,rotational suspension separation, polymerization at liquid-gas orsolid-gas interface, pressure extrusion, or spraying solvent extractionbath. In addition to these, several chemical techniques, e.g., complexcoacervation, solvent evaporation, polymer-polymer incompatibility,interfacial polymerization in liquid media, in situ polymerization,in-liquid drying, and desolvation in liquid media could also be used.Furthermore, other methods such as roller compaction,extrusion/spheronization, coacervation, or nanoparticle coating may alsobe used.

In some embodiments, the particles of compounds of any of Formula(I)-(XLIIIc) are microencapsulated prior to being formulated into one ofthe above forms. In still some embodiments, some or most of theparticles are coated prior to being further formulated by using standardcoating procedures, such as those described in Remington'sPharmaceutical Sciences, 20th Edition (2000).

In some embodiments, the solid dosage formulations of the compounds ofany of Formula (I)-(XLIIIc) are plasticized (coated) with one or morelayers. Illustratively, a plasticizer is generally a high boiling pointsolid or liquid. Suitable plasticizers can be added from about 0.01% toabout 50% by weight (w/w) of the coating composition. Plasticizersinclude, but are not limited to, diethyl phthalate, citrate esters,polyethylene glycol, glycerol, acetylated glycerides, triacetin,polypropylene glycol, polyethylene glycol, triethyl citrate, dibutylsebacate, stearic acid, stearol, stearate, and castor oil.

In some embodiments, a powder including the formulations with a compoundof any of Formula (I)-(XVII), described herein, may be formulated toinclude one or more pharmaceutical excipients and flavors. Such a powdermay be prepared, for example, by mixing the formulation and optionalpharmaceutical excipients to form a bulk blend composition. Additionalembodiments also include a suspending agent and/or a wetting agent. Thisbulk blend is uniformly subdivided into unit dosage packaging ormulti-dosage packaging units.

In still some embodiments, effervescent powders are also prepared inaccordance with the present disclosure. Effervescent salts have beenused to disperse medicines in water for oral administration.Effervescent salts are granules or coarse powders containing a medicinalagent in a dry mixture, usually composed of sodium bicarbonate, citricacid and/or tartaric acid. When salts of the compositions describedherein are added to water, the acids and the base react to liberatecarbon dioxide gas, thereby causing “effervescence.” Examples ofeffervescent salts include, e.g., the following ingredients: sodiumbicarbonate or a mixture of sodium bicarbonate and sodium carbonate,citric acid and/or tartaric acid. Any acid-base combination that resultsin the liberation of carbon dioxide can be used in place of thecombination of sodium bicarbonate and citric and tartaric acids, as longas the ingredients were suitable for pharmaceutical use and result in apH of about 6.0 or higher.

In some embodiments, the formulations described herein, which include acompound of Formula (A), are solid dispersions. Methods of producingsuch solid dispersions are known in the art and include, but are notlimited to, for example, U.S. Pat. Nos. 4,343,789, 5,340,591, 5,456,923,5,700,485, 5,723,269, and U.S. Pub. Appl 2004/0013734, each of which isspecifically incorporated by reference. In some embodiments, theformulations described herein are solid solutions. Solid solutionsincorporate a substance together with the active agent and otherexcipients such that heating the mixture results in dissolution of thedrug and the resulting composition is then cooled to provide a solidblend which can be further formulated or directly added to a capsule orcompressed into a tablet. Methods of producing such solid solutions areknown in the art and include, but are not limited to, for example, U.S.Pat. Nos. 4,151,273, 5,281,420, and 6,083,518, each of which isspecifically incorporated by reference.

The pharmaceutical solid oral dosage forms including formulationsdescribed herein, which include a compound of any of Formula(I)-(XLIIIc) can be further formulated to provide a controlled releaseof the compound of Formula (A). Controlled release refers to the releaseof the compound of any of Formula (I)-(XLIIIc) from a dosage form inwhich it is incorporated according to a desired profile over an extendedperiod of time. Controlled release profiles include, for example,sustained release, prolonged release, pulsatile release, and delayedrelease profiles. In contrast to immediate release compositions,controlled release compositions allow delivery of an agent to a subjectover an extended period of time according to a predetermined profile.Such release rates can provide therapeutically effective levels of agentfor an extended period of time and thereby provide a longer period ofpharmacologic response while minimizing side effects as compared toconventional rapid release dosage forms. Such longer periods of responseprovide for many inherent benefits that are not achieved with thecorresponding short acting, immediate release preparations.

In some embodiments, the solid dosage forms described herein can beformulated as enteric coated delayed release oral dosage forms, i.e., asan oral dosage form of a pharmaceutical composition as described hereinwhich utilizes an enteric coating to affect release in the smallintestine of the gastrointestinal tract. The enteric coated dosage formmay be a compressed or molded or extruded tablet/mold (coated oruncoated) containing granules, powder, pellets, beads or particles ofthe active ingredient and/or other composition components, which arethemselves coated or uncoated. The enteric coated oral dosage form mayalso be a capsule (coated or uncoated) containing pellets, beads orgranules of the solid carrier or the composition, which are themselvescoated or uncoated.

The term “delayed release” as used herein refers to the delivery so thatthe release can be accomplished at some generally predictable locationin the intestinal tract more distal to that which would have beenaccomplished if there had been no delayed release alterations. In someembodiments the method for delay of release is coating. Any coatingsshould be applied to a sufficient thickness such that the entire coatingdoes not dissolve in the gastrointestinal fluids at pH below about 5,but does dissolve at pH about 5 and above. It is expected that anyanionic polymer exhibiting a pH-dependent solubility profile can be usedas an enteric coating in the methods and compositions described hereinto achieve delivery to the lower gastrointestinal tract. In someembodiments the polymers described herein are anionic carboxylicpolymers. In some embodiments, the polymers and compatible mixturesthereof, and some of their properties, include, but are not limited to:

Shellac, also called purified lac, a refined product obtained from theresinous secretion of an insect. This coating dissolves in media ofpH>7;

Acrylic polymers. The performance of acrylic polymers (primarily theirsolubility in biological fluids) can vary based on the degree and typeof substitution. Examples of suitable acrylic polymers includemethacrylic acid copolymers and ammonium methacrylate copolymers. TheEudragit series E, L, S, RL, RS and NE (Rohm Pharma) are available assolubilized in organic solvent, aqueous dispersion, or dry powders. TheEudragit series RL, NE, and RS are insoluble in the gastrointestinaltract but are permeable and are used primarily for colonic targeting.The Eudragit series E dissolve in the stomach. The Eudragit series L,L-30D and S are insoluble in stomach and dissolve in the intestine;

Cellulose Derivatives. Examples of suitable cellulose derivatives are:ethyl cellulose; reaction mixtures of partial acetate esters ofcellulose with phthalic anhydride. The performance can vary based on thedegree and type of substitution. Cellulose acetate phthalate (CAP)dissolves in pH>6. Aquateric (FMC) is an aqueous based system and is aspray dried CAP psuedolatex with particles <1 m. Other components inAquateric can include pluronics, Tweens, and acetylated monoglycerides.Other suitable cellulose derivatives include: cellulose acetatetrimellitate (Eastman); methylcellulose (Pharmacoat, Methocel);hydroxypropylmethyl cellulose phthalate (HPMCP); hydroxypropylmethylcellulose succinate (HPMCS); and hydroxypropylmethylcellulose acetatesuccinate (e.g., AQOAT (Shin Etsu)). The performance can vary based onthe degree and type of substitution. For example, HPMCP such as, HP-50,HP-55, HP-55S, HP-55F grades are suitable. The performance can varybased on the degree and type of substitution. For example, suitablegrades of hydroxypropylmethylcellulose acetate succinate include, butare not limited to, AS-LG (LF), which dissolves at pH 5, AS-MG (MF),which dissolves at pH 5.5, and AS-HG (HF), which dissolves at higher pH.These polymers are offered as granules, or as fine powders for aqueousdispersions;

Poly Vinyl Acetate Phthalate (PVAP). PVAP dissolves in pH>5, and it ismuch less permeable to water vapor and gastric fluids.

In some embodiments, the coating can, and usually does, contain aplasticizer and possibly other coating excipients such as colorants,talc, and/or magnesium stearate, which are well known in the art.Suitable plasticizers include triethyl citrate (Citroflex 2), triacetin(glyceryl triacetate), acetyl triethyl citrate (Citroflec A2), Carbowax400 (polyethylene glycol 400), diethyl phthalate, tributyl citrate,acetylated monoglycerides, glycerol, fatty acid esters, propyleneglycol, and dibutyl phthalate. In particular, anionic carboxylic acrylicpolymers usually will contain 10-25% by weight of a plasticizer,especially dibutyl phthalate, polyethylene glycol, triethyl citrate andtriacetin. Conventional coating techniques such as spray or pan coatingare employed to apply coatings. The coating thickness must be sufficientto ensure that the oral dosage form remains intact until the desiredsite of topical delivery in the intestinal tract is reached.

Colorants, detackifiers, surfactants, antifoaming agents, lubricants(e.g., carnuba wax or PEG) may be added to the coatings besidesplasticizers to solubilize or disperse the coating material, and toimprove coating performance and the coated product.

In some embodiments, the formulations described herein, which include acompound of Formula (A), are delivered using a pulsatile dosage form. Apulsatile dosage form is capable of providing one or more immediaterelease pulses at predetermined time points after a controlled lag timeor at specific sites. Pulsatile dosage forms including the formulationsdescribed herein, which include a compound of any of Formula(I)-(XLIIIc) may be administered using a variety of pulsatileformulations known in the art. For example, such formulations include,but are not limited to, those described in U.S. Pat. Nos. 5,011,692,5,017,381, 5,229,135, and 5,840,329, each of which is specificallyincorporated by reference. Other pulsatile release dosage forms suitablefor use with the present formulations include, but are not limited to,for example, U.S. Pat. Nos. 4,871,549, 5,260,068, 5,260,069, 5,508,040,5,567,441 and 5,837,284, all of which are specifically incorporated byreference. In some embodiments, the controlled release dosage form ispulsatile release solid oral dosage form including at least two groupsof particles, (i.e. multiparticulate) each containing the formulationdescribed herein. The first group of particles provides a substantiallyimmediate dose of the compound of any of Formula (I)-(XLIIIc) uponingestion by a mammal. The first group of particles can be eitheruncoated or include a coating and/or sealant. The second group ofparticles includes coated particles, which includes from about 2% toabout 75%, from about 2.5% to about 70%, or from about 40% to about 70%,by weight of the total dose of the compound of any of Formula(I)-(XLIIIc) in said formulation, in admixture with one or more binders.The coating includes a pharmaceutically acceptable ingredient in anamount sufficient to provide a delay of from about 2 hours to about 7hours following ingestion before release of the second dose. Suitablecoatings include one or more differentially degradable coatings such as,by way of example only, pH sensitive coatings (enteric coatings) such asacrylic resins (e.g., Eudragit® EPO, Eudragit® L30D-55, Eudragit® FS 30DEudragit® L100-55, Eudragit® L100, Eudragit® S100, Eudragit® RD100,Eudragit® E100, Eudragit® L12.5, Eudragit® S12.5, and Eudragit® NE30D,Eudragit® NE 40D®) either alone or blended with cellulose derivatives,e.g., ethylcellulose, or non-enteric coatings having variable thicknessto provide differential release of the formulation that includes acompound of any of Formula (I).

Many other types of controlled release systems known to those ofordinary skill in the art and are suitable for use with the formulationsdescribed herein. Examples of such delivery systems include, e.g.,polymer-based systems, such as polylactic and polyglycolic acid,plyanhydrides and polycaprolactone; porous matrices, nonpolymer-basedsystems that are lipids, including sterols, such as cholesterol,cholesterol esters and fatty acids, or neutral fats, such as mono-, di-and triglycerides; hydrogel release systems; silastic systems;peptide-based systems; wax coatings, bioerodible dosage forms,compressed tablets using conventional binders and the like. See, e.g.,Liberman et al., Pharmaceutical Dosage Forms, 2 Ed., Vol. 1, pp. 209-214(1990); Singh et al., Encyclopedia of Pharmaceutical Technology, 2^(nd)Ed., pp. 751-753 (2002); U.S. Pat. Nos. 4,327,725, 4,624,848, 4,968,509,5,461,140, 5,456,923, 5,516,527, 5,622,721, 5,686,105, 5,700,410,5,977,175, 6,465,014 and 6,932,983, each of which is specificallyincorporated by reference.

In some embodiments, pharmaceutical compositions are provided thatinclude particles of the compounds of any of Formula (I)-(XVII),described herein and at least one dispersing agent or suspending agentfor oral administration to a subject. The formulations may be a powderand/or granules for suspension, and upon admixture with water, asubstantially uniform suspension is obtained.

Liquid formulation dosage forms for oral administration can be aqueoussuspensions selected from the group including, but not limited to,pharmaceutically acceptable aqueous oral dispersions, emulsions,solutions, elixirs, gels, and syrups. See, e.g., Singh et al.,Encyclopedia of Pharmaceutical Technology, 2^(nd) Ed., pp. 754-757(2002). In addition to the particles of compound of Formula (A), theliquid dosage forms may include additives, such as: (a) disintegratingagents; (b) dispersing agents; (c) wetting agents; (d) at least onepreservative, (e) viscosity enhancing agents, (f) at least onesweetening agent, and (g) at least one flavoring agent. In someembodiments, the aqueous dispersions can further include a crystallineinhibitor.

The aqueous suspensions and dispersions described herein can remain in ahomogenous state, as defined in The USP Pharmacists' Pharmacopeia (2005edition, chapter 905), for at least 4 hours. The homogeneity should bedetermined by a sampling method consistent with regard to determininghomogeneity of the entire composition. In some embodiments, an aqueoussuspension can be re-suspended into a homogenous suspension by physicalagitation lasting less than 1 minute. In some embodiments, an aqueoussuspension can be re-suspended into a homogenous suspension by physicalagitation lasting less than 45 seconds. In yet some embodiments, anaqueous suspension can be re-suspended into a homogenous suspension byphysical agitation lasting less than 30 seconds. In still someembodiments, no agitation is necessary to maintain a homogeneous aqueousdispersion.

Examples of disintegrating agents for use in the aqueous suspensions anddispersions include, but are not limited to, a starch, e.g., a naturalstarch such as corn starch or potato starch, a pregelatinized starchsuch as National 1551 or Amijel®, or sodium starch glycolate such asPromogel® or Explotab®; a cellulose such as a wood product,methylcrystalline cellulose, e.g., Avicel®, Avicel® PH101, Avicel®PH102, Avicel® PH105, Elcema® P100, Emcocel®, Vivacel®, Ming Tia®, andSolka-Floc®, methylcellulose, croscarmellose, or a cross-linkedcellulose, such as cross-linked sodium carboxymethylcellulose(Ac-Di-Sol®), cross-linked carboxymethylcellulose, or cross-linkedcroscarmellose; a cross-linked starch such as sodium starch glycolate; across-linked polymer such as crospovidone; a cross-linkedpolyvinylpyrrolidone; alginate such as alginic acid or a salt of alginicacid such as sodium alginate; a clay such as Veegum® HV (magnesiumaluminum silicate); a gum such as agar, guar, locust bean, Karaya,pectin, or tragacanth; sodium starch glycolate; bentonite; a naturalsponge; a surfactant; a resin such as a cation-exchange resin; citruspulp; sodium lauryl sulfate; sodium lauryl sulfate in combinationstarch; and the like.

In some embodiments, the dispersing agents suitable for the aqueoussuspensions and dispersions described herein are known in the art andinclude, for example, hydrophilic polymers, electrolytes, Tween® 60 or80, PEG, polyvinylpyrrolidone (PVP; commercially known as Plasdone®),and the carbohydrate-based dispersing agents such as, for example,hydroxypropylcellulose and hydroxypropyl cellulose ethers (e.g., HPC,HPC-SL, and HPC-L), hydroxypropyl methylcellulose and hydroxypropylmethylcellulose ethers (e.g. HPMC K100, HPMC K4M, HPMC K15M, and HPMCK100M), carboxymethylcellulose sodium, methylcellulose,hydroxyethylcellulose, hydroxypropylmethyl-cellulose phthalate,hydroxypropylmethyl-cellulose acetate stearate, noncrystallinecellulose, magnesium aluminum silicate, triethanolamine, polyvinylalcohol (PVA), polyvinylpyrrolidone/vinyl acetate copolymer (Plasdone®,e.g., S-630), 4-(1,1,3,3-tetramethylbutyl)-phenol polymer with ethyleneoxide and formaldehyde (also known as tyloxapol), poloxamers (e.g.,Pluronics F68®, F88®, and F108®, which are block copolymers of ethyleneoxide and propylene oxide); and poloxamines (e.g., Tetronic 908®, alsoknown as Poloxamine 908®, which is a tetrafunctional block copolymerderived from sequential addition of propylene oxide and ethylene oxideto ethylenediamine (BASF Corporation, Parsippany, N.J.)). In someembodiments, the dispersing agent is selected from a group notcomprising one of the following agents: hydrophilic polymers;electrolytes; Tween® 60 or 80; PEG; polyvinylpyrrolidone (PVP);hydroxypropylcellulose and hydroxypropyl cellulose ethers (e.g., HPC,HPC-SL, and HPC-L); hydroxypropyl methylcellulose and hydroxypropylmethylcellulose ethers (e.g. HPMC K100, HPMC K4M, HPMC K15M, HPMC K100M,and Pharmacoat® USP 2910 (Shin-Etsu)); carboxymethylcellulose sodium;methylcellulose; hydroxyethylcellulose; hydroxypropylmethyl-cellulosephthalate; hydroxypropylmethyl-cellulose acetate stearate;non-crystalline cellulose; magnesium aluminum silicate; triethanolamine;polyvinyl alcohol (PVA); 4-(1,1,3,3-tetramethylbutyl)-phenol polymerwith ethylene oxide and formaldehyde; poloxamers (e.g., Pluronics F68®,F88®, and F108®, which are block copolymers of ethylene oxide andpropylene oxide); or poloxamines (e.g., Tetronic 908®, also known asPoloxamine 908®).

Wetting agents suitable for the aqueous suspensions and dispersionsdescribed herein are known in the art and include, but are not limitedto, cetyl alcohol, glycerol monostearate, polyoxyethylene sorbitan fattyacid esters (e.g., the commercially available Tweens® such as e.g.,Tween 20® and Tween 80® (ICI Specialty Chemicals)), and polyethyleneglycols (e.g., Carbowaxs 3350® and 1450®, and Carbopol 934® (UnionCarbide)), oleic acid, glyceryl monostearate, sorbitan monooleate,sorbitan monolaurate, triethanolamine oleate, polyoxyethylene sorbitanmonooleate, polyoxyethylene sorbitan monolaurate, sodium oleate, sodiumlauryl sulfate, sodium docusate, triacetin, vitamin E TPGS, sodiumtaurocholate, simethicone, phosphotidylcholine and the like

Suitable preservatives for the aqueous suspensions or dispersionsdescribed herein include, for example, potassium sorbate, parabens(e.g., methylparaben and propylparaben), benzoic acid and its salts,other esters of parahydroxybenzoic acid such as butylparaben, alcoholssuch as ethyl alcohol or benzyl alcohol, phenolic compounds such asphenol, or quaternary compounds such as benzalkonium chloride.Preservatives, as used herein, are incorporated into the dosage form ata concentration sufficient to inhibit microbial growth.

Suitable viscosity enhancing agents for the aqueous suspensions ordispersions described herein include, but are not limited to, methylcellulose, xanthan gum, carboxymethyl cellulose, hydroxypropylcellulose, hydroxypropylmethyl cellulose, Plasdon® S-630, carbomer,polyvinyl alcohol, alginates, acacia, chitosans and combinationsthereof. The concentration of the viscosity enhancing agent will dependupon the agent selected and the viscosity desired.

Examples of sweetening agents suitable for the aqueous suspensions ordispersions described herein include, for example, acacia syrup,acesulfame K, alitame, anise, apple, aspartame, banana, Bavarian cream,berry, black currant, butterscotch, calcium citrate, camphor, caramel,cherry, cherry cream, chocolate, cinnamon, bubble gum, citrus, citruspunch, citrus cream, cotton candy, cocoa, cola, cool cherry, coolcitrus, cyclamate, cylamate, dextrose, eucalyptus, eugenol, fructose,fruit punch, ginger, glycyrrhetinate, glycyrrhiza (licorice) syrup,grape, grapefruit, honey, isomalt, lemon, lime, lemon cream,monoammonium glyrrhizinate (MagnaSweet®), maltol, mannitol, maple,marshmallow, menthol, mint cream, mixed berry, neohesperidine DC,neotame, orange, pear, peach, peppermint, peppermint cream, Prosweet®Powder, raspberry, root beer, rum, saccharin, safrole, sorbitol,spearmint, spearmint cream, strawberry, strawberry cream, stevia,sucralose, sucrose, sodium saccharin, saccharin, aspartame, acesulfamepotassium, mannitol, talin, sucralose, sorbitol, swiss cream, tagatose,tangerine, thaumatin, tutti fruitti, vanilla, walnut, watermelon, wildcherry, wintergreen, xylitol, or any combination of these flavoringingredients, e.g., anise-menthol, cherry-anise, cinnamon-orange,cherry-cinnamon, chocolate-mint, honey-lemon, lemon-lime, lemon-mint,menthol-eucalyptus, orange-cream, vanilla-mint, and mixtures thereof. Insome embodiments, the aqueous liquid dispersion can comprise asweetening agent or flavoring agent in a concentration ranging fromabout 0.001% to about 1.0% the volume of the aqueous dispersion. In someembodiments, the aqueous liquid dispersion can comprise a sweeteningagent or flavoring agent in a concentration ranging from about 0.005% toabout 0.5% the volume of the aqueous dispersion. In yet someembodiments, the aqueous liquid dispersion can comprise a sweeteningagent or flavoring agent in a concentration ranging from about 0.01% toabout 1.0% the volume of the aqueous dispersion.

In addition to the additives listed above, the liquid formulations canalso include inert diluents commonly used in the art, such as water orother solvents, solubilizing agents, and emulsifiers. Exemplaryemulsifiers are ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethylacetate, benzyl alcohol, benzyl benzoate, propyleneglycol,1,3-butyleneglycol, dimethylformamide, sodium lauryl sulfate, sodiumdoccusate, cholesterol, cholesterol esters, taurocholic acid,phosphotidylcholine, oils, such as cottonseed oil, groundnut oil, corngerm oil, olive oil, castor oil, and sesame oil, glycerol,tetrahydrofurfuryl alcohol, polyethylene glycols, fatty acid esters ofsorbitan, or mixtures of these substances, and the like.

In some embodiments, the pharmaceutical compositions described hereincan be self-emulsifying drug delivery systems (SEDDS). Emulsions aredispersions of one immiscible phase in another, usually in the form ofdroplets. Generally, emulsions are created by vigorous mechanicaldispersion. SEDDS, as opposed to emulsions or microemulsions,spontaneously form emulsions when added to an excess of water withoutany external mechanical dispersion or agitation. An advantage of SEDDSis that only gentle mixing is required to distribute the dropletsthroughout the solution. Additionally, water or the aqueous phase can beadded just prior to administration, which ensures stability of anunstable or hydrophobic active ingredient. Thus, the SEDDS provides aneffective delivery system for oral and parenteral delivery ofhydrophobic active ingredients. SEDDS may provide improvements in thebioavailability of hydrophobic active ingredients. Methods of producingself-emulsifying dosage forms are known in the art and include, but arenot limited to, for example, U.S. Pat. Nos. 5,858,401, 6,667,048, and6,960,563, each of which is specifically incorporated by reference.

It is to be appreciated that there is overlap between the above-listedadditives used in the aqueous dispersions or suspensions describedherein, since a given additive is often classified differently bydifferent practitioners in the field, or is commonly used for any ofseveral different functions. Thus, the above-listed additives should betaken as merely exemplary, and not limiting, of the types of additivesthat can be included in formulations described herein. The amounts ofsuch additives can be readily determined by one skilled in the art,according to the particular properties desired.

Intranasal Formulations

Intranasal formulations are known in the art and are described in, forexample, U.S. Pat. Nos. 4,476,116, 5,116,817 and 6,391,452, each ofwhich is specifically incorporated by reference. Formulations thatinclude a compound of any of Formula (I)-(XLIIIc) which are preparedaccording to these and other techniques well-known in the art areprepared as solutions in saline, employing benzyl alcohol or othersuitable preservatives, fluorocarbons, and/or other solubilizing ordispersing agents known in the art. See, for example, Ansel, H. C. etal., Pharmaceutical Dosage Forms and Drug Delivery Systems, Sixth Ed.(1995). Preferably these compositions and formulations are prepared withsuitable nontoxic pharmaceutically acceptable ingredients. Theseingredients are known to those skilled in the preparation of nasaldosage forms and some of these can be found in Remington: The Scienceand Practice of Pharmacy, 21st edition, 2005, a standard reference inthe field. The choice of suitable carriers is highly dependent upon theexact nature of the nasal dosage form desired, e.g., solutions,suspensions, ointments, or gels. Nasal dosage forms generally containlarge amounts of water in addition to the active ingredient. Minoramounts of other ingredients such as pH adjusters, emulsifiers ordispersing agents, preservatives, surfactants, gelling agents, orbuffering and other stabilizing and solubilizing agents may also bepresent. The nasal dosage form should be isotonic with nasal secretions.

For administration by inhalation, the compounds of any of Formula(I)-(XVII), described herein may be in a form as an aerosol, a mist or apowder. Pharmaceutical compositions described herein are convenientlydelivered in the form of an aerosol spray presentation from pressurizedpacks or a nebuliser, with the use of a suitable propellant, e.g.,dichlorodifluoromethane, trichlorofluoromethane,dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In thecase of a pressurized aerosol, the dosage unit may be determined byproviding a valve to deliver a metered amount. Capsules and cartridgesof, such as, by way of example only, gelatin for use in an inhaler orinsufflator may be formulated containing a powder mix of the compounddescribed herein and a suitable powder base such as lactose or starch.

Buccal Formulations

Buccal formulations that include compounds of any of Formula(I)-(XLIIIc) may be administered using a variety of formulations knownin the art. For example, such formulations include, but are not limitedto, U.S. Pat. Nos. 4,229,447, 4,596,795, 4,755,386, and 5,739,136, eachof which is specifically incorporated by reference. In addition, thebuccal dosage forms described herein can further include a bioerodible(hydrolysable) polymeric carrier that also serves to adhere the dosageform to the buccal mucosa. The buccal dosage form is fabricated so as toerode gradually over a predetermined time period, wherein the deliveryof the compound of any of Formula (I)-(XVII), is provided essentiallythroughout. Buccal drug delivery, as will be appreciated by thoseskilled in the art, avoids the disadvantages encountered with oral drugadministration, e.g., slow absorption, degradation of the active agentby fluids present in the gastrointestinal tract and/or first-passinactivation in the liver. With regard to the bioerodible (hydrolysable)polymeric carrier, it will be appreciated that virtually any suchcarrier can be used, so long as the desired drug release profile is notcompromised, and the carrier is compatible with the compound of any ofFormula (I)-(XVII), and any other components that may be present in thebuccal dosage unit. Generally, the polymeric carrier compriseshydrophilic (water-soluble and water-swellable) polymers that adhere tothe wet surface of the buccal mucosa. Examples of polymeric carriersuseful herein include acrylic acid polymers and co, e.g., those known as“carbomers” (Carbopol®, which may be obtained from B.F. Goodrich, is onesuch polymer). Other components may also be incorporated into the buccaldosage forms described herein include, but are not limited to,disintegrants, diluents, binders, lubricants, flavoring, colorants,preservatives, and the like. For buccal or sublingual administration,the compositions may take the form of tablets, lozenges, or gelsformulated in a conventional manner.

Transdermal Formulations

Transdermal formulations described herein may be administered using avariety of devices which have been described in the art. For example,such devices include, but are not limited to, U.S. Pat. Nos. 3,598,122,3,598,123, 3,710,795, 3,731,683, 3,742,951, 3,814,097, 3,921,636,3,972,995, 3,993,072, 3,993,073, 3,996,934, 4,031,894, 4,060,084,4,069,307, 4,077,407, 4,201,211, 4,230,105, 4,292,299, 4,292,303,5,336,168, 5,665,378, 5,837,280, 5,869,090, 6,923,983, 6,929,801 and6,946,144, each of which is specifically incorporated by reference inits entirety.

The transdermal dosage forms described herein may incorporate certainpharmaceutically acceptable excipients which are conventional in theart. In some embodiments, the transdermal formulations described hereininclude at least three components: (1) a formulation of a compound ofany of Formula (I); (2) a penetration enhancer; and (3) an aqueousadjuvant. In addition, transdermal formulations can include additionalcomponents such as, but not limited to, gelling agents, creams andointment bases, and the like. In some embodiments, the transdermalformulation can further include a woven or non-woven backing material toenhance absorption and prevent the removal of the transdermalformulation from the skin. In some embodiments, the transdermalformulations described herein can maintain a saturated or supersaturatedstate to promote diffusion into the skin.

Formulations suitable for transdermal administration of compoundsdescribed herein may employ transdermal delivery devices and transdermaldelivery patches and can be lipophilic emulsions or buffered, aqueoussolutions, dissolved and/or dispersed in a polymer or an adhesive. Suchpatches may be constructed for continuous, pulsatile, or on demanddelivery of pharmaceutical agents. Still further, transdermal deliveryof the compounds described herein can be accomplished by means ofiontophoretic patches and the like. Additionally, transdermal patchescan provide controlled delivery of the compounds of any of Formula(I)-(XVII). The rate of absorption can be slowed by usingrate-controlling membranes or by trapping the compound within a polymermatrix or gel. Conversely, absorption enhancers can be used to increaseabsorption. An absorption enhancer or carrier can include absorbablepharmaceutically acceptable solvents to assist passage through the skin.For example, transdermal devices are in the form of a bandage comprisinga backing member, a reservoir containing the compound optionally withcarriers, optionally a rate controlling barrier to deliver the compoundto the skin of the host at a controlled and predetermined rate over aprolonged period of time, and means to secure the device to the skin.

Injectable Formulations

Formulations that include a compound of any of Formula (I)-(XVII),suitable for intramuscular, subcutaneous, or intravenous injection mayinclude physiologically acceptable sterile aqueous or non-aqueoussolutions, dispersions, suspensions or emulsions, and sterile powdersfor reconstitution into sterile injectable solutions or dispersions.Examples of suitable aqueous and non-aqueous carriers, diluents,solvents, or vehicles including water, ethanol, polyols(propyleneglycol, polyethylene-glycol, glycerol, cremophor and thelike), suitable mixtures thereof, vegetable oils (such as olive oil) andinjectable organic esters such as ethyl oleate. Proper fluidity can bemaintained, for example, by the use of a coating such as lecithin, bythe maintenance of the required particle size in the case ofdispersions, and by the use of surfactants. Formulations suitable forsubcutaneous injection may also contain additives such as preserving,wetting, emulsifying, and dispensing agents. Prevention of the growth ofmicroorganisms can be ensured by various antibacterial and antifungalagents, such as parabens, chlorobutanol, phenol, sorbic acid, and thelike. It may also be desirable to include isotonic agents, such assugars, sodium chloride, and the like. Prolonged absorption of theinjectable pharmaceutical form can be brought about by the use of agentsdelaying absorption, such as aluminum monostearate and gelatin.

For intravenous injections, compounds described herein may be formulatedin aqueous solutions, preferably in physiologically compatible bufferssuch as Hank's solution, Ringer's solution, or physiological salinebuffer. For transmucosal administration, penetrants appropriate to thebarrier to be permeated are used in the formulation. Such penetrants aregenerally known in the art. For other parenteral injections, appropriateformulations may include aqueous or nonaqueous solutions, preferablywith physiologically compatible buffers or excipients. Such excipientsare generally known in the art.

Parenteral injections may involve bolus injection or continuousinfusion. Formulations for injection may be presented in unit dosageform, e.g., in ampoules or in multi-dose containers, with an addedpreservative. The pharmaceutical composition described herein may be ina form suitable for parenteral injection as a sterile suspensions,solutions or emulsions in oily or aqueous vehicles, and may containformulatory agents such as suspending, stabilizing and/or dispersingagents. Pharmaceutical compositions for parenteral administrationinclude aqueous solutions of the active compounds in water-soluble form.Additionally, suspensions of the active compounds may be prepared asappropriate oily injection suspensions. Suitable lipophilic solvents orvehicles include fatty oils such as sesame oil, or synthetic fatty acidesters, such as ethyl oleate or triglycerides, or liposomes. Aqueousinjection suspensions may contain substances which increase theviscosity of the suspension, such as sodium carboxymethyl cellulose,sorbitol, or dextran. Optionally, the suspension may also containsuitable stabilizers or agents which increase the solubility of thecompounds to allow for the preparation of highly concentrated solutions.Alternatively, the active ingredient may be in powder form forconstitution with a suitable vehicle, e.g., sterile pyrogen-free water,before use.

Formulations

In certain embodiments, delivery systems for pharmaceutical compoundsmay be employed, such as, for example, liposomes and emulsions. Incertain embodiments, compositions provided herein can also include anmucoadhesive polymer, selected from among, for example,carboxymethylcellulose, carbomer (acrylic acid polymer),poly(methylmethacrylate), polyacrylamide, polycarbophil, acrylicacid/butyl acrylate copolymer, sodium alginate and dextran.

In some embodiments, the compounds described herein may be administeredtopically and can be formulated into a variety of topicallyadministrable compositions, such as solutions, suspensions, lotions,gels, pastes, medicated sticks, balms, creams or ointments. Suchpharmaceutical compounds can contain solubilizers, stabilizers, tonicityenhancing agents, buffers and preservatives.

The compounds described herein may also be formulated in rectalcompositions such as enemas, rectal gels, rectal foams, rectal aerosols,suppositories, jelly suppositories, or retention enemas, containingconventional suppository bases such as cocoa butter or other glycerides,as well as synthetic polymers such as polyvinylpyrrolidone, PEG, and thelike. In suppository forms of the compositions, a low-melting wax suchas, but not limited to, a mixture of fatty acid glycerides, optionallyin combination with cocoa butter is first melted.

Examples of Methods of Dosing and Treatment Regimens

The compounds described herein can be used in the preparation ofmedicaments for the inhibition of menin or a homolog thereof, or for thetreatment of diseases or conditions that would benefit, at least inpart, from inhibition of menin or a homolog thereof. In addition, amethod for treating any of the diseases or conditions described hereinin a subject in need of such treatment, involves administration ofpharmaceutical compositions containing at least one compound of any ofFormula (I)-(XVII), described herein, or a pharmaceutically acceptablesalt, pharmaceutically acceptable N-oxide, pharmaceutically activemetabolite, pharmaceutically acceptable prodrug, or pharmaceuticallyacceptable solvate thereof, in therapeutically effective amounts to saidsubject.

The compositions containing the compound(s) described herein can beadministered for prophylactic and/or therapeutic treatments. Intherapeutic applications, the compositions are administered to a patientalready suffering from a disease or condition, in an amount sufficientto cure or at least partially arrest the symptoms of the disease orcondition. Amounts effective for this use will depend on the severityand course of the disease or condition, previous therapy, the patient'shealth status, weight, and response to the drugs, and the judgment ofthe treating physician. It is considered well within the skill of theart for one to determine such therapeutically effective amounts byroutine experimentation (including, but not limited to, a doseescalation clinical trial).

In prophylactic applications, compositions containing the compoundsdescribed herein are administered to a patient susceptible to orotherwise at risk of a particular disease, disorder or condition. Suchan amount is defined to be a “prophylactically effective amount ordose.” In this use, the precise amounts also depend on the patient'sstate of health, weight, and the like. It is considered well within theskill of the art for one to determine such prophylactically effectiveamounts by routine experimentation (e.g., a dose escalation clinicaltrial). When used in a patient, effective amounts for this use willdepend on the severity and course of the disease, disorder or condition,previous therapy, the patient's health status and response to the drugs,and the judgment of the treating physician.

In the case wherein the patient's condition does not improve, upon thedoctor's discretion the administration of the compounds may beadministered chronically, that is, for an extended period of time,including throughout the duration of the patient's life in order toameliorate or otherwise control or limit the symptoms of the patient'sdisease or condition.

In the case wherein the patient's status does improve, upon the doctor'sdiscretion the administration of the compounds may be givencontinuously; alternatively, the dose of drug being administered may betemporarily reduced or temporarily suspended for a certain length oftime (i.e., a “drug holiday”). The length of the drug holiday can varybetween 2 days and 1 year, including by way of example only, 2 days, 3days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20days, 28 days, 35 days, 50 days, 70 days, 100 days, 120 days, 150 days,180 days, 200 days, 250 days, 280 days, 300 days, 320 days, 350 days, or365 days. The dose reduction during a drug holiday may be from 10%-100%,including, by way of example only, 10%, 15%, 20%, 25%, 30%, 35%, 40%,45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%.

Once improvement of the patient's conditions has occurred, a maintenancedose is administered if necessary. Subsequently, the dosage or thefrequency of administration, or both, can be reduced, as a function ofthe symptoms, to a level at which the improved disease, disorder orcondition is retained. Patients can, however, require intermittenttreatment on a long-term basis upon any recurrence of symptoms.

The amount of a given agent that will correspond to such an amount willvary depending upon factors such as the particular compound, disease orcondition and its severity, the identity (e.g., weight) of the subjector host in need of treatment, but can nevertheless be routinelydetermined in a manner known in the art according to the particularcircumstances surrounding the case, including, e.g., the specific agentbeing administered, the route of administration, the condition beingtreated, and the subject or host being treated. In general, however,doses employed for adult human treatment will typically be in the rangeof 0.02-5000 mg per day, or from about 1-1500 mg per day. The desireddose may conveniently be presented in a single dose or as divided dosesadministered simultaneously (or over a short period of time) or atappropriate intervals, for example as two, three, four or more sub-dosesper day.

The pharmaceutical composition described herein may be in unit dosageforms suitable for single administration of precise dosages. In unitdosage form, the formulation is divided into unit doses containingappropriate quantities of one or more compound. The unit dosage may bein the form of a package containing discrete quantities of theformulation. Non-limiting examples are packaged tablets or capsules, andpowders in vials or ampoules. Aqueous suspension compositions can bepackaged in single-dose non-reclosable containers. Alternatively,multiple-dose reclosable containers can be used, in which case it istypical to include a preservative in the composition. By way of exampleonly, formulations for parenteral injection may be presented in unitdosage form, which include, but are not limited to ampoules, or inmulti-dose containers, with an added preservative.

The foregoing ranges are merely suggestive, as the number of variablesin regard to an individual treatment regime is large, and considerableexcursions from these recommended values are not uncommon. Such dosagesmay be altered depending on a number of variables, not limited to theactivity of the compound used, the disease or condition to be treated,the mode of administration, the requirements of the individual subject,the severity of the disease or condition being treated, and the judgmentof the practitioner.

Toxicity and therapeutic efficacy of such therapeutic regimens can bedetermined by standard pharmaceutical procedures in cell cultures orexperimental animals, including, but not limited to, the determinationof the LD₅₀ (the dose lethal to 50% of the population) and the ED₅₀ (thedose therapeutically effective in 50% of the population). The dose ratiobetween the toxic and therapeutic effects is the therapeutic index andit can be expressed as the ratio between LD₅₀ and ED₅₀. Compoundsexhibiting high therapeutic indices are preferred. The data obtainedfrom cell culture assays and animal studies can be used in formulating arange of dosage for use in human. The dosage of such compounds liespreferably within a range of circulating concentrations that include theED₅₀ with minimal toxicity. The dosage may vary within this rangedepending upon the dosage form employed and the route of administrationutilized.

Combination Treatments

The Menin-MLL inhibitor compositions described herein can also be usedin combination with other well known therapeutic reagents that areselected for their therapeutic value for the condition to be treated. Ingeneral, the compositions described herein and, in embodiments wherecombinational therapy is employed, other agents do not have to beadministered in the same pharmaceutical composition, and may, because ofdifferent physical and chemical characteristics, have to be administeredby different routes. The determination of the mode of administration andthe advisability of administration, where possible, in the samepharmaceutical composition, is well within the knowledge of the skilledclinician. The initial administration can be made according toestablished protocols known in the art, and then, based upon theobserved effects, the dosage, modes of administration and times ofadministration can be modified by the skilled clinician.

In certain instances, it may be appropriate to administer at least oneMenin-MLL inhibitor compound described herein in combination withanother therapeutic agent. By way of example only, if one of the sideeffects experienced by a patient upon receiving one of the Menin-MLLinhibitor compounds described herein is nausea, then it may beappropriate to administer an anti-nausea agent in combination with theinitial therapeutic agent. Or, by way of example only, the therapeuticeffectiveness of one of the compounds described herein may be enhancedby administration of an adjuvant (i.e., by itself the adjuvant may haveminimal therapeutic benefit, but in combination with another therapeuticagent, the overall therapeutic benefit to the patient is enhanced). Or,by way of example only, the benefit experienced by a patient may beincreased by administering one of the compounds described herein withanother therapeutic agent (which also includes a therapeutic regimen)that also has therapeutic benefit. In any case, regardless of thedisease, disorder or condition being treated, the overall benefitexperienced by the patient may simply be additive of the two therapeuticagents or the patient may experience a synergistic benefit.

The particular choice of compounds used will depend upon the diagnosisof the attending physicians and their judgment of the condition of thepatient and the appropriate treatment protocol. The compounds may beadministered concurrently (e.g., simultaneously, essentiallysimultaneously or within the same treatment protocol) or sequentially,depending upon the nature of the disease, disorder, or condition, thecondition of the patient, and the actual choice of compounds used. Thedetermination of the order of administration, and the number ofrepetitions of administration of each therapeutic agent during atreatment protocol, is well within the knowledge of the skilledphysician after evaluation of the disease being treated and thecondition of the patient.

It is known to those of skill in the art that therapeutically-effectivedosages can vary when the drugs are used in treatment combinations.Methods for experimentally determining therapeutically-effective dosagesof drugs and other agents for use in combination treatment regimens aredescribed in the literature. For example, the use of metronomic dosing,i.e., providing more frequent, lower doses in order to minimize toxicside effects, has been described extensively in the literatureCombination treatment further includes periodic treatments that startand stop at various times to assist with the clinical management of thepatient.

For combination therapies described herein, dosages of theco-administered compounds will of course vary depending on the type ofco-drug employed, on the specific drug employed, on the disease orcondition being treated and so forth. In addition, when co-administeredwith one or more biologically active agents, the compound providedherein may be administered either simultaneously with the biologicallyactive agent(s), or sequentially. If administered sequentially, theattending physician will decide on the appropriate sequence ofadministering protein in combination with the biologically activeagent(s).

In any case, the multiple therapeutic agents (one of which is a compoundof Formula (I)-(XVII), described herein) may be administered in anyorder or even simultaneously. If simultaneously, the multipletherapeutic agents may be provided in a single, unified form, or inmultiple forms (by way of example only, either as a single pill or astwo separate pills). One of the therapeutic agents may be given inmultiple doses, or both may be given as multiple doses. If notsimultaneous, the timing between the multiple doses may vary from morethan zero weeks to less than four weeks. In addition, the combinationmethods, compositions and formulations are not to be limited to the useof only two agents; the use of multiple therapeutic combinations arealso envisioned.

It is understood that the dosage regimen to treat, prevent, orameliorate the condition(s) for which relief is sought, can be modifiedin accordance with a variety of factors. These factors include thedisorder from which the subject suffers, as well as the age, weight,sex, diet, and medical condition of the subject. Thus, the dosageregimen actually employed can vary widely and therefore can deviate fromthe dosage regimens set forth herein.

The pharmaceutical agents which make up the combination therapydisclosed herein may be a combined dosage form or in separate dosageforms intended for substantially simultaneous administration. Thepharmaceutical agents that make up the combination therapy may also beadministered sequentially, with either therapeutic compound beingadministered by a regimen calling for two-step administration. Thetwo-step administration regimen may call for sequential administrationof the active agents or spaced-apart administration of the separateactive agents. The time period between the multiple administration stepsmay range from, a few minutes to several hours, depending upon theproperties of each pharmaceutical agent, such as potency, solubility,bioavailability, plasma half-life and kinetic profile of thepharmaceutical agent. Circadian variation of the target moleculeconcentration may also determine the optimal dose interval.

In addition, the compounds described herein also may be used incombination with procedures that may provide additional or synergisticbenefit to the patient. By way of example only, patients are expected tofind therapeutic and/or prophylactic benefit in the methods describedherein, wherein pharmaceutical composition of a compound disclosedherein and/or combinations with other therapeutics are combined withgenetic testing to determine whether that individual is a carrier of amutant gene that is known to be correlated with certain diseases orconditions.

The compounds described herein and combination therapies can beadministered before, during or after the occurrence of a disease orcondition, and the timing of administering the composition containing acompound can vary. Thus, for example, the compounds can be used as aprophylactic and can be administered continuously to subjects with apropensity to develop conditions or diseases in order to prevent theoccurrence of the disease or condition. The compounds and compositionscan be administered to a subject during or as soon as possible after theonset of the symptoms. The administration of the compounds can beinitiated within the first 48 hours of the onset of the symptoms, withinthe first 6 hours of the onset of the symptoms, or within 3 hours of theonset of the symptoms. The initial administration can be via any routepractical, such as, for example, an intravenous injection, a bolusinjection, infusion over 5 minutes to about 5 hours, a pill, a capsule,transdermal patch, buccal delivery, and the like, or combinationthereof. A compound should be administered as soon as is practicableafter the onset of a disease or condition is detected or suspected, andfor a length of time necessary for the treatment of the disease, suchas, for example, from about 1 month to about 3 months. The length oftreatment can vary for each subject, and the length can be determinedusing the known criteria. For example, the compound or a formulationcontaining the compound can be administered for at least 2 weeks,between about 1 month to about 5 years, or from about 1 month to about 3years.

Exemplary Therapeutic Agents for Use in Combination with an Menin-MLLInhibitor Compound

Where the subject is suffering from or at risk of suffering from anautoimmune disease, an inflammatory disease, or an allergy disease, anMenin-MLL inhibitor compound can be used in with one or more of thefollowing therapeutic agents in any combination: immunosuppressants(e.g., tacrolimus, cyclosporin, rapamicin, methotrexate,cyclophosphamide, azathioprine, mercaptopurine, mycophenolate, orFTY720), glucocorticoids (e.g., prednisone, cortisone acetate,prednisolone, methylprednisolone, dexamethasone, betamethasone,triamcinolone, beclometasone, fludrocortisone acetate,deoxycorticosterone acetate, aldosterone), non-steroidalanti-inflammatory drugs (e.g., salicylates, arylalkanoic acids,2-arylpropionic acids, N-arylanthranilic acids, oxicams, coxibs, orsulphonanilides), Cox-2-specific irreversible inhibitors (e.g.,valdecoxib, celecoxib, or rofecoxib), leflunomide, gold thioglucose,gold thiomalate, aurofin, sulfasalazine, hydroxychloroquinine,minocycline, TNF-α binding proteins (e.g., infliximab, etanercept, oradalimumab), abatacept, anakinra, interferon-β, interferon-γ,interleukin-2, allergy vaccines, antihistamines, antileukotrienes,beta-agonists, theophylline, or anticholinergics.

Where the subject is suffering from or at risk of suffering from aB-cell proliferative disorder (e.g., plasma cell myeloma), the subjectedcan be treated with an Menin-MLL inhibitor compound in any combinationwith one or more other anti-cancer agents. In some embodiments, one ormore of the anti-cancer agents are proapoptotic agents. Examples ofanti-cancer agents include, but are not limited to, any of thefollowing: gossyphol, genasense, polyphenol E, Chlorofusin, alltrans-retinoic acid (ATRA), bryostatin, tumor necrosis factor-relatedapoptosis-inducing ligand (TRAIL), 5-aza-2′-deoxycytidine, all transretinoic acid, doxorubicin, vincristine, etoposide, gemcitabine,imatinib (Gleevec®), geldanamycin,17-N-Allylamino-17-Demethoxygeldanamycin (17-AAG), flavopiridol,LY294002, bortezomib, trastuzumab, BAY 11-7082, PKC412, or PD184352,Taxol™, also referred to as “paclitaxel”, which is a well-knownanti-cancer drug which acts by enhancing and stabilizing microtubuleformation, and analogs of Taxol™, such as Taxotere™. Compounds that havethe basic taxane skeleton as a common structure feature, have also beenshown to have the ability to arrest cells in the G2-M phases due tostabilized microtubules and may be useful for treating cancer incombination with the compounds described herein.

Other anti-cancer agents that can be employed in combination with anMenin-MLL inhibitor compound include Adriamycin, Dactinomycin,Bleomycin, Vinblastine, Cisplatin, acivicin; aclarubicin; acodazolehydrochloride; acronine; adozelesin; aldesleukin; altretamine;ambomycin; ametantrone acetate; aminoglutethimide; amsacrine;anastrozole; anthramycin; asparaginase; asperlin; azacitidine; azetepa;azotomycin; batimastat; benzodepa; bicalutamide; bisantrenehydrochloride; bisnafide dimesylate; bizelesin; bleomycin sulfate;brequinar sodium; bropirimine; busulfan; cactinomycin; calusterone;caracemide; carbetimer; carboplatin; carmustine; carubicinhydrochloride; carzelesin; cedefingol; chlorambucil; cirolemycin;cladribine; crisnatol mesylate; cyclophosphamide; cytarabine;dacarbazine; daunorubicin hydrochloride; decitabine; dexormaplatin;dezaguanine; dezaguanine mesylate; diaziquone; doxorubicin; doxorubicinhydrochloride; droloxifene; droloxifene citrate; dromostanolonepropionate; duazomycin; edatrexate; eflornithine hydrochloride;elsamitrucin; enloplatin; enpromate; epipropidine; epirubicinhydrochloride; erbulozole; esorubicin hydrochloride; estramustine;estramustine phosphate sodium; etanidazole; etoposide; etoposidephosphate; etoprine; fadrozole hydrochloride; fazarabine; fenretinide;floxuridine; fludarabine phosphate; fluorouracil; flurocitabine;fosquidone; fostriecin sodium; gemcitabine; gemcitabine hydrochloride;hydroxyurea; idarubicin hydrochloride; ifosfamide; iimofosine;interleukin Il (including recombinant interleukin II, or rlL2),interferon α-2a; interferon α-2b; interferon α-n1; interferon α-n3;interferon β-la; interferon γ-lb; iproplatin; irinotecan hydrochloride;lanreotide acetate; letrozole; leuprolide acetate; liarozolehydrochloride; lometrexol sodium; lomustine; losoxantrone hydrochloride;masoprocol; maytansine; mechlorethamine hydrochloride; megestrolacetate; melengestrol acetate; melphalan; menogaril; mercaptopurine;methotrexate; methotrexate sodium; metoprine; meturedepa; mitindomide;mitocarcin; mitocromin; mitogillin; mitomalcin; mitomycin; mitosper;mitotane; mitoxantrone hydrochloride; mycophenolic acid; nocodazoie;nogalamycin; ormaplatin; oxisuran; pegaspargase; peliomycin;pentamustine; peplomycin sulfate; perfosfamide; pipobroman; piposulfan;piroxantrone hydrochloride; plicamycin; plomestane; porfimer sodium;porfiromycin; prednimustine; procarbazine hydrochloride; puromycin;puromycin hydrochloride; pyrazofurin; riboprine; rogletimide; safingol;safingol hydrochloride; semustine; simtrazene; sparfosate sodium;sparsomycin; spirogermanium hydrochloride; spiromustine; spiroplatin;streptonigrin; streptozocin; sulofenur; talisomycin; tecogalan sodium;tegafur; teloxantrone hydrochloride; temoporfin; teniposide; teroxirone;testolactone; thiamiprine; thioguanine; thiotepa; tiazofurin;tirapazamine; toremifene citrate; trestolone acetate; triciribinephosphate; trimetrexate; trimetrexate glucuronate; triptorelin;tubulozole hydrochloride; uracil mustard; uredepa; vapreotide;verteporfin; vinblastine sulfate; vincristine sulfate; vindesine;vindesine sulfate; vinepidine sulfate; vinglycinate sulfate;vinleurosine sulfate; vinorelbine tartrate; vinrosidine sulfate;vinzolidine sulfate; vorozole; zeniplatin; zinostatin; zorubicinhydrochloride.

Other anti-cancer agents that can be employed in combination with anMenin-MLL inhibitor compound include: 20-epi-1, 25 dihydroxyvitamin D3;5-ethynyluracil; abiraterone; aclarubicin; acylfulvene; adecypenol;adozelesin; aldesleukin; ALL-TK antagonists; altretamine; ambamustine;amidox; amifostine; aminolevulinic acid; amrubicin; amsacrine;anagrelide; anastrozole; andrographolide; angiogenesis irreversibleinhibitors; antagonist D; antagonist G; antarelix; anti-dorsalizingmorphogenetic protein-1; antiandrogen, prostatic carcinoma;antiestrogen; antineoplaston; antisense oligonucleotides; aphidicolinglycinate; apoptosis gene modulators; apoptosis regulators; apurinicacid; ara-CDP-DL-PTBA; arginine deaminase; asulacrine; atamestane;atrimustine; axinastatin 1; axinastatin 2; axinastatin 3; azasetron;azatoxin; azatyrosine; baccatin III derivatives; balanol; batimastat;BCR/ABL antagonists; benzochlorins; benzoylstaurosporine; beta lactamderivatives; beta-alethine; betaclamycin B; betulinic acid; bFGFinhibitor; bicalutamide; bisantrene; bisaziridinylspermine; bisnafide;bistratene A; bizelesin; breflate; bropirimine; budotitane; buthioninesulfoximine; calcipotriol; calphostin C; camptothecin derivatives;canarypox IL-2; capecitabine; carboxamide-amino-triazole;carboxyamidotriazole; CaRest M3; CARN 700; cartilage derived inhibitor;carzelesin; casein kinase irreversible inhibitors (ICOS);castanospermine; cecropin B; cetrorelix; chlorlns; chloroquinoxalinesulfonamide; cicaprost; cis-porphyrin; cladribine; clomifene analogues;clotrimazole; collismycin A; collismycin B; combretastatin A4;combretastatin analogue; conagenin; crambescidin 816; crisnatol;cryptophycin 8; cryptophycin A derivatives; curacin A;cyclopentanthraquinones; cycloplatam; cypemycin; cytarabine ocfosfate;cytolytic factor; cytostatin; dacliximab; decitabine; dehydrodidemnin B;deslorelin; dexamethasone; dexifosfamide; dexrazoxane; dexverapamil;diaziquone; didemnin B; didox; diethylnorspermine;dihydro-5-azacytidine; 9-dioxamycin; diphenyl spiromustine; docosanol;dolasetron; doxifluridine; droloxifene; dronabinol; duocarmycin SA;ebselen; ecomustine; edelfosine; edrecolomab; eflornithine; elemene;emitefur; epirubicin; epristeride; estramustine analogue; estrogenagonists; estrogen antagonists; etanidazole; etoposide phosphate;exemestane; fadrozole; fazarabine; fenretinide; filgrastim; finasteride;flavopiridol; flezelastine; fluasterone; fludarabine; fluorodaunorunicinhydrochloride; forfenimex; formestane; fostriecin; fotemustine;gadolinium texaphyrin; gallium nitrate; galocitabine; ganirelix;gelatinase irreversible inhibitors; gemcitabine; glutathioneirreversible inhibitors; hepsulfam; heregulin; hexamethylenebisacetamide; hypericin; ibandronic acid; idarubicin; idoxifene;idramantone; ilmofosine; ilomastat; imidazoacridones; imiquimod;immunostimulant peptides; insulin-like growth factor-1 receptorinhibitor; interferon agonists; interferons; interleukins; iobenguane;iododoxorubicin; ipomeanol, 4-; iroplact; irsogladine; isobengazole;isohomohalicondrin B; itasetron; jasplakinolide; kahalalide F;lamellarin-N triacetate; lanreotide; leinamycin; lenograstim; lentinansulfate; leptolstatin; letrozole; leukemia inhibiting factor; leukocytealpha interferon; leuprolide+estrogen+progesterone; leuprorelin;levamisole; liarozole; linear polyamine analogue; lipophilicdisaccharide peptide; lipophilic platinum compounds; lissoclinamide 7;lobaplatin; lombricine; lometrexol; lonidamine; losoxantrone;lovastatin; loxoribine; lurtotecan; lutetium texaphyrin; lysofylline;lytic peptides; maitansine; mannostatin A; marimastat; masoprocol;maspin; matrilysin irreversible inhibitors; matrix metalloproteinaseirreversible inhibitors; menogaril; merbarone; meterelin; methioninase;metoclopramide; MIF inhibitor; mifepristone; miltefosine; mirimostim;mismatched double stranded RNA; mitoguazone; mitolactol; mitomycinanalogues; mitonafide; mitotoxin fibroblast growth factor-saporin;mitoxantrone; mofarotene; molgramostim; monoclonal antibody, humanchorionic gonadotrophin; monophosphoryl lipid A+myobacterium cell wallsk; mopidamol; multiple drug resistance gene inhibitor; multiple tumorsuppressor 1-based therapy; mustard anticancer agent; mycaperoxide B;mycobacterial cell wall extract; myriaporone; N-acetyldinaline;N-substituted benzamides; nafarelin; nagrestip; naloxone+pentazocine;napavin; naphterpin; nartograstim; nedaplatin; nemorubicin; neridronicacid; neutral endopeptidase; nilutamide; nisamycin; nitric oxidemodulators; nitroxide antioxidant; nitrullyn; O6-benzylguanine;octreotide; okicenone; oligonucleotides; onapristone; ondansetron;ondansetron; oracin; oral cytokine inducer; ormaplatin; osaterone;oxaliplatin; oxaunomycin; palauamine; palmitoylrhizoxin; pamidronicacid; panaxytriol; panomifene; parabactin; pazelliptine; pegaspargase;peldesine; pentosan polysulfate sodium; pentostatin; pentrozole;perflubron; perfosfamide; perillyl alcohol; phenazinomycin;phenylacetate; phosphatase irreversible inhibitors; picibanil;pilocarpine hydrochloride; pirarubicin; piritrexim; placetin A; placetinB; plasminogen activator inhibitor; platinum complex; platinumcompounds; platinum-triamine complex; porfimer sodium; porfiromycin;prednisone; propyl bis-acridone; prostaglandin J2; proteasomeirreversible inhibitors; protein A-based immune modulator; proteinkinase C inhibitor; protein kinase C irreversible inhibitors,microalgal; protein tyrosine phosphatase irreversible inhibitors; purinenucleoside phosphorylase irreversible inhibitors; purpurins;pyrazoloacridine; pyridoxylated hemoglobin polyoxyethylerie conjugate;raf antagonists; raltitrexed; ramosetron; ras farnesyl proteintransferase irreversible inhibitors; ras irreversible inhibitors;ras-GAP inhibitor; retelliptine demethylated; rhenium Re 186 etidronate;rhizoxin; ribozymes; RII retinamide; rogletimide; rohitukine; romurtide;roquinimex; rubiginone B1; ruboxyl; safingol; saintopin; SarCNU;sarcophytol A; sargramostim; Sdi 1 mimetics; semustine; senescencederived inhibitor 1; sense oligonucleotides; signal transductionirreversible inhibitors; signal transduction modulators; single chainantigen-binding protein; sizofiran; sobuzoxane; sodium borocaptate;sodium phenylacetate; solverol; somatomedin binding protein; sonermin;sparfosic acid; spicamycin D; spiromustine; splenopentin; spongistatin1; squalamine; stem cell inhibitor; stem-cell division irreversibleinhibitors; stipiamide; stromelysin irreversible inhibitors;sulfinosine; superactive vasoactive intestinal peptide antagonist;suradista; suramin; swainsonine; synthetic glycosaminoglycans;tallimustine; tamoxifen methiodide; tauromustine; tazarotene; tecogalansodium; tegafur; tellurapyrylium; telomerase irreversible inhibitors;temoporfin; temozolomide; teniposide; tetrachlorodecaoxide; tetrazomine;thaliblastine; thiocoraline; thrombopoietin; thrombopoietin mimetic;thymalfasin; thymopoietin receptor agonist; thymotrinan; thyroidstimulating hormone; tin ethyl etiopurpurin; tirapazamine; titanocenebichloride; topsentin; toremifene; totipotent stem cell factor;translation irreversible inhibitors; tretinoin; triacetyluridine;triciribine; trimetrexate; triptorelin; tropisetron; turosteride;tyrosine kinase irreversible inhibitors; tyrphostins; UBC irreversibleinhibitors; ubenimex; urogenital sinus-derived growth inhibitory factor;urokinase receptor antagonists; vapreotide; variolin B; vector system,erythrocyte gene therapy; velaresol; veramine; verdins; verteporfin;vinorelbine; vinxaltine; vitaxin; vorozole; zanoterone; zeniplatin;zilascorb; and zinostatin stimalamer.

Yet other anticancer agents that can be employed in combination with anMenin-MLL inhibitor compound include alkylating agents, antimetabolites,natural products, or hormones, e.g., nitrogen mustards (e.g.,mechloroethamine, cyclophosphamide, chlorambucil, etc.), alkylsulfonates (e.g., busulfan), nitrosoureas (e.g., carmustine, lomusitne,etc.), or triazenes (decarbazine, etc.). Examples of antimetabolitesinclude but are not limited to folic acid analog (e.g., methotrexate),or pyrimidine analogs (e.g., Cytarabine), purine analogs (e.g.,mercaptopurine, thioguanine, pentostatin).

Examples of natural products useful in combination with an Menin-MLLinhibitor compound include but are not limited to vinca alkaloids (e.g.,vinblastin, vincristine), epipodophyllotoxins (e.g., etoposide),antibiotics (e.g., daunorubicin, doxorubicin, bleomycin), enzymes (e.g.,L-asparaginase), or biological response modifiers (e.g., interferonalpha).

Examples of alkylating agents that can be employed in combination anMenin-MLL inhibitor compound include, but are not limited to, nitrogenmustards (e.g., mechloroethamine, cyclophosphamide, chlorambucil,meiphalan, etc.), ethylenimine and methylmelamines (e.g.,hexamethlymelamine, thiotepa), alkyl sulfonates (e.g., busulfan),nitrosoureas (e.g., carmustine, lomusitne, semustine, streptozocin,etc.), or triazenes (decarbazine, etc.). Examples of antimetabolitesinclude, but are not limited to folic acid analog (e.g., methotrexate),or pyrimidine analogs (e.g., fluorouracil, floxouridine, Cytarabine),purine analogs (e.g., mercaptopurine, thioguanine, pentostatin.

Examples of hormones and antagonists useful in combination with anMenin-MLL inhibitor compound include, but are not limited to,adrenocorticosteroids (e.g., prednisone), progestins (e.g.,hydroxyprogesterone caproate, megestrol acetate, medroxyprogesteroneacetate), estrogens (e.g., diethlystilbestrol, ethinyl estradiol),antiestrogen (e.g., tamoxifen), androgens (e.g., testosteronepropionate, fluoxymesterone), antiandrogen (e.g., flutamide),gonadotropin releasing hormone analog (e.g., leuprolide). Other agentsthat can be used in the methods and compositions described herein forthe treatment or prevention of cancer include platinum coordinationcomplexes (e.g., cisplatin, carboblatin), anthracenedione (e.g.,mitoxantrone), substituted urea (e.g., hydroxyurea), methyl hydrazinederivative (e.g., procarbazine), adrenocortical suppressant (e.g.,mitotane, aminoglutethimide).

Examples of anti-cancer agents which act by arresting cells in the G2-Mphases due to stabilized microtubules and which can be used incombination with an Menin-MLL inhibitor compound include withoutlimitation the following marketed drugs and drugs in development:Erbulozole (also known as R-55104), Dolastatin 10 (also known as DLS-10and NSC-376128), Mivobulin isethionate (also known as CI-980),Vincristine, NSC-639829, Discodermolide (also known as NVP-XX-A-296),ABT-751 (Abbott, also known as E-7010), Altorhyrtins (such asAltorhyrtin A and Altorhyrtin C), Spongistatins (such as Spongistatin 1,Spongistatin 2, Spongistatin 3, Spongistatin 4, Spongistatin 5,Spongistatin 6, Spongistatin 7, Spongistatin 8, and Spongistatin 9),Cemadotin hydrochloride (also known as LU-103793 and NSC-D-669356),Epothilones (such as Epothilone A, Epothilone B, Epothilone C (alsoknown as desoxyepothilone A or dEpoA), Epothilone D (also referred to asKOS-862, dEpoB, and desoxyepothilone B), Epothilone E, Epothilone F,Epothilone B N-oxide, Epothilone A N-oxide, 16-aza-epothilone B,21-aminoepothilone B (also known as BMS-310705), 21-hydroxyepothilone D(also known as Desoxyepothilone F and dEpoF), 26-fluoroepothilone),Auristatin PE (also known as NSC-654663), Soblidotin (also known asTZT-1027), LS-4559-P (Pharmacia, also known as LS-4577), LS-4578(Pharmacia, also known as LS-477-P), LS-4477 (Pharmacia), LS-4559(Pharmacia), RPR-112378 (Aventis), Vincristine sulfate, DZ-3358(Daiichi), FR-182877 (Fujisawa, also known as WS-9885B), GS-164(Takeda), GS-198 (Takeda), KAR-2 (Hungarian Academy of Sciences),BSF-223651 (BASF, also known as ILX-651 and LU-223651), SAH-49960(Lilly/Novartis), SDZ-268970 (Lilly/Novartis), AM-97 (Armad/KyowaHakko), AM-132 (Armad), AM-138 (Armad/Kyowa Hakko), IDN-5005 (Indena),Cryptophycin 52 (also known as LY-355703), AC-7739 (Ajinomoto, alsoknown as AVE-8063A and CS-39.HCI), AC-7700 (Ajinomoto, also known asAVE-8062, AVE-8062A, CS-39-L-Ser.HCI, and RPR-258062A), Vitilevuamide,Tubulysin A, Canadensol, Centaureidin (also known as NSC-106969),T-138067 (Tularik, also known as T-67, TL-138067 and TI-138067), COBRA-1(Parker Hughes Institute, also known as DDE-261 and WHI-261), H10(Kansas State University), H16 (Kansas State University), Oncocidin A1(also known as BTO-956 and DIME), DDE-313 (Parker Hughes Institute),Fijianolide B, Laulimalide, SPA-2 (Parker Hughes Institute), SPA-1(Parker Hughes Institute, also known as SPIKET-P), 3-IAABU(Cytoskeleton/Mt. Sinai School of Medicine, also known as MF-569),Narcosine (also known as NSC-5366), Nascapine, D-24851 (Asta Medica),A-105972 (Abbott), Hemiasterlin, 3-BAABU (Cytoskeleton/Mt. Sinai Schoolof Medicine, also known as MF-191), TMPN (Arizona State University),Vanadocene acetylacetonate, T-138026 (Tularik), Monsatrol, lnanocine(also known as NSC-698666), 3-lAABE (Cytoskeleton/Mt. Sinai School ofMedicine), A-204197 (Abbott), T-607 (Tuiarik, also known as T-900607),RPR-(Aventis), Eleutherobins (such as Desmethyleleutherobin,Desaetyleleutherobin, lsoeleutherobin A, and Z-Eleutherobin),Caribaeoside, Caribaeolin, Halichondrin B, D-64131 (Asta Medica),D-68144 (Asta Medica), Diazonamide A, A-293620 (Abbott), NPI-2350(Nereus), Taccalonolide A, TUB-245 (Aventis), A-259754 (Abbott),Diozostatin, (−)-Phenylahistin (also known as NSCL-96F037), D-68838(Asta Medica), D-68836 (Asta Medica), Myoseverin B, D-43411 (Zentaris,also known as D-81862), A-289099 (Abbott), A-318315 (Abbott), HTI-286(also known as SPA-110, trifluoroacetate salt) (Wyeth), D-82317(Zentaris), D-82318 (Zentaris), SC-12983 (NCI), Resverastatin phosphatesodium, BPR-OY-007 (National Health Research Institutes), and SSR-250411(Sanofi).

Where the subject is suffering from or at risk of suffering from athromboembolic disorder (e.g., stroke), the subject can be treated withan Menin-MLL inhibitor compound in any combination with one or moreother anti-thromboembolic agents. Examples of anti-thromboembolic agentsinclude, but are not limited any of the following: thrombolytic agents(e.g., alteplase anistreplase, streptokinase, urokinase, or tissueplasminogen activator), heparin, tinzaparin, warfarin, dabigatran (e.g.,dabigatran etexilate), factor Xa irreversible inhibitors (e.g.,fondaparinux, draparinux, rivaroxaban, DX-9065a, otamixaban, LY517717,or YM150), ticlopidine, clopidogrel, CS-747 (prasugrel, LY640315),ximelagatran, or BIBR 1048.

Kits/Articles of Manufacture

For use in the therapeutic applications described herein, kits andarticles of manufacture are also described herein. Such kits can includea carrier, package, or container that is compartmentalized to receiveone or more containers such as vials, tubes, and the like, each of thecontainer(s) including one of the separate elements to be used in amethod described herein. Suitable containers include, for example,bottles, vials, syringes, and test tubes. The containers can be formedfrom a variety of materials such as glass or plastic.

The articles of manufacture provided herein contain packaging materials.Packaging materials for use in packaging pharmaceutical products arewell known to those of skill in the art. See, e.g., U.S. Pat. Nos.5,323,907, 5,052,558 and 5,033,252. Examples of pharmaceutical packagingmaterials include, but are not limited to, blister packs, bottles,tubes, inhalers, pumps, bags, vials, containers, syringes, bottles, andany packaging material suitable for a selected formulation and intendedmode of administration and treatment. A wide array of formulations ofthe compounds and compositions provided herein are contemplated as are avariety of treatments for any disease, disorder, or condition that wouldbenefit by inhibition of menin, or in which menin is a mediator orcontributor to the symptoms or cause.

For example, the container(s) can include one or more compoundsdescribed herein, optionally in a composition or in combination withanother agent as disclosed herein. The container(s) optionally have asterile access port (for example the container can be an intravenoussolution bag or a vial having a stopper pierceable by a hypodermicinjection needle). Such kits optionally comprising a compound with anidentifying description or label or instructions relating to its use inthe methods described herein.

A kit will typically may include one or more additional containers, eachwith one or more of various materials (such as reagents, optionally inconcentrated form, and/or devices) desirable from a commercial and userstandpoint for use of a compound described herein. Non-limiting examplesof such materials include, but not limited to, buffers, diluents,filters, needles, syringes; carrier, package, container, vial and/ortube labels listing contents and/or instructions for use, and packageinserts with instructions for use. A set of instructions will alsotypically be included.

A label can be on or associated with the container. A label can be on acontainer when letters, numbers or other characters forming the labelare attached, molded or etched into the container itself, a label can beassociated with a container when it is present within a receptacle orcarrier that also holds the container, e.g., as a package insert. Alabel can be used to indicate that the contents are to be used for aspecific therapeutic application. The label can also indicate directionsfor use of the contents, such as in the methods described herein.

In certain embodiments, the pharmaceutical compositions can be presentedin a pack or dispenser device which can contain one or more unit dosageforms containing a compound provided herein. The pack can for examplecontain metal or plastic foil, such as a blister pack. The pack ordispenser device can be accompanied by instructions for administration.The pack or dispenser can also be accompanied with a notice associatedwith the container in form prescribed by a governmental agencyregulating the manufacture, use, or sale of pharmaceuticals, whichnotice is reflective of approval by the agency of the form of the drugfor human or veterinary administration. Such notice, for example, can bethe labeling approved by the U.S. Food and Drug Administration forprescription drugs, or the approved product insert. Compositionscontaining a compound provided herein formulated in a compatiblepharmaceutical carrier can also be prepared, placed in an appropriatecontainer, and labeled for treatment of an indicated condition.

Examples

The following specific and non-limiting examples are to be construed asmerely illustrative, and do not limit the present disclosure in any waywhatsoever. Without further elaboration, it is believed that one skilledin the art can, based on the description herein, utilize the presentdisclosure to its fullest extent. All publications cited herein arehereby incorporated by reference in their entirety. Where reference ismade to a URL or other such identifier or address, it is understood thatsuch identifiers can change and particular information on the internetcan come and go, but equivalent information can be found by searchingthe internet. Reference thereto evidences the availability and publicdissemination of such information.

The examples below as well as throughout the application, the followingabbreviations have the following meanings. If not defined, the termshave their generally accepted meanings.

-   -   aq=aqueous    -   Boc=tert-butyloxycarbonyl    -   t-BuOH=tertiary butanol    -   DCE=1,2-dichloroethane    -   DCM=dichloromethane    -   DIAD=diisopropyl azodicarboxylate    -   DIEA or DIPEA=N,N-diisopropylethylamine    -   DMAP=dimethylaminopyridine    -   DMF=dimethylformamide    -   DMSO=dimethylsulfoxide    -   ESI=electron spray ionization    -   EA=ethyl acetate    -   g=gram    -   HCl=hydrogen chloride    -   HPLC=high performance liquid chromatography    -   hr=hour    -   ¹H NMR=proton nuclear magnetic resonance    -   IPA=isopropyl alcohol    -   KOAc=potassium acetate    -   LC-MS=liquid chromatography mass spectroscopy    -   M=molar    -   MeCN=acetonitrile    -   MeOH=methanol    -   mg=milligram    -   min=minute    -   ml=milliliter    -   mM=millimolar    -   mmol=millimole    -   m.p.=melting point    -   MS=mass spectrometry    -   m/z=mass-to-charge ratio    -   N=normal    -   NIS=N-iodosuccinimide    -   nM=nanomolar    -   nm=nanometer    -   Pd(dppf)Cl₂=[1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II)    -   PE=petroleum ether    -   PyBOP=benzotriazol-1-yl-oxytripyrrolidinophosphonium        hexafluorophosphate    -   quant.=quantitative    -   RP=reverse phase    -   rt or r.t.=room temperature    -   Sat.=saturated    -   TEA=triethylamine    -   TFA=trifluoroacetic acid    -   μL=microliter    -   μM=Micromolar

wherein Cy, Cy², L, R², R^(6a), R^(6b), and R^(6c) are as describedherein.Generic Synthetic for Intermediate 3A and/or 5A

General Procedure for Preparation of Intermediate 3A

To a solution of morpholine (3.12 g, 35.7 mmol, 3.15 mL, 2 eq) wasreacted with Intermediate 1A (5.00 g, 17.8 mmol, 1 eq) in n-butanol(25.0 mL) at 100° C. for 12 h. The color of the solution become white.TLC (Dichloromethane/Methanol=10/1, R_(f)=0.60) indicated the startingmaterial was consumed completely. The reaction mixture was diluted withH₂O (200.0 mL) and extracted with EtOAc (100.0 mL×3). The combinedorganic layers were washed with brine (100.0 mL), dried over Na₂SO₄,filtered and concentrated under reduced pressure to give a residue. Thecompound was used for the next step without further purification. NMRshowed Intermediate 3A (5.08 g, 15.3 mmol, 86.0% yield) was obtained asa white solid

General Procedure for Preparation of Intermediate 5A

A solution of (4-aminophenyl)boronic acid (2.49 g, 18.1 mmol, 1.5 eq),Intermediate 3A (4.00 g, 12.1 mmol, 1 eq) and K₂CO₃ (10.0 g, 72.7 mmol,6 eq) in dioxane (20.0 mL) and H₂O (4.00 mL) was degassed with argon 30min and cyclopentyl(diphenyl)phosphane; dichloropalladium; iron (886.5mg, 1.21 mmol, 0.1 eq) was added the reacter. The mixture was refluxedat 100° C. for 12 h. The color of the solution become black. TLC(Dichloromethane/Methanol=10/1, R_(f)=0.57) indicated the startingmaterial was consumed completely. The reaction mixture was diluted withH₂O (300.0 mL) and extracted with EtOAc (300.0 mL×3). The combinedorganic layers were washed with brine (300.0 mL), dried over Na₂SO₄,filtered and concentrated under reduced pressure to give a residue. Theresidue was purified by column chromatography (SiO₂, Petroleumether/Ethyl acetate=50/1 to 5/1) Intermediate 5A (3.00 g, 10.1 mmol,83.8% yield) was obtained as a white solid.

EXAMPLES Example 1 Synthesis of Compound 1

General Procedure for Preparation of Intermediate 3

A mixture of Intermediate 1 (11.0 g, 69.3 mmol, 1 eq), Intermediate 2(21.7 g, 104.0 mmol, 1.5 eq, HCl) and NaHCO₃ (14.5 g, 173.4 mmol, 6.75mL, 2.5 eq) in DMSO (100.0 mL) was stirred at 70° C. for 16 h. TLC(Petroleum ether/Ethyl acetate=1/1, R_(f)=0.24) indicated the startingmaterial was consumed completely. The reaction mixtures were combined,and then diluted with H₂O (50.0 mL) and extracted with EtOAc (20.0mL×3). The combined organic layers were washed with H₂O (50.0 mL×5) andbrine (20.0 mL), dried over Na₂SO₄, filtered and concentrated underreduced pressure to give a residue. The residue was purified by columnchromatography (SiO₂, Petroleum ether/Ethyl acetate=20/1 to 1/1).Intermediate 3 (15.0 g, 50.9 mmol, 73.4% yield) was obtained as a yellowsolid.

¹H NMR. MeOD Varian_Y_400 MHz

8.07 (d, J=5.7 Hz, 1H), 7.19 (d, J=2.2 Hz, 1H), 6.66 (dd, J=2.2, 5.7 Hz,1H), 4.60 (br s, 1H), 4.37 (t, J=8.2 Hz, 2H), 3.93 (dd, J=5.6, 8.5 Hz,2H), 1.45 (s, 9H)

General Procedure for Preparation of Intermediate 4

To a solution of Intermediate 3 (13.0 g, 44.1 mmol, 1 eq) in MeOH (80.0mL) was added Pd/C (5.00 g, 10% purity) under N₂. The suspension wasdegassed under vacuum and purged with H₂ several times. The mixture wasstirred under H₂ (50 psi) at 25° C. for 2 h. TLC(Dichloromethane/Methanol=10/1, R_(f)=0.24) indicated Reactant 1 wasconsumed completely and a new spot formed. The reaction mixture wasfiltered and the filter was concentrated to give the residue. Theresidue was washed with DCM/EtOAc=1/2 (100.0 mL). Intermediate 4 (8.00g, 30.2 mmol, 68.5% yield) was obtained as a white solid.

¹H NMR: DMSO Varian_S_400 MHz

7.55 (d, J=5.7 Hz, 2H), 5.65 (dd, J=1.8, 5.7 Hz, 1H), 5.43 (s, 2H), 5.36(d, J=1.5 Hz, 1H), 4.34-4.45 (m, 1H), 4.02 (t, J=7.6 Hz, 2H), 3.53-3.60(m, 2H), 1.38 (s, 9H)

General Procedure for Preparation of Intermediate 5

To solution of Intermediate 5A (1.00 g, 3.39 mmol, 1 eq) in THF (30.0mL) was added K₂CO₃ (1.40 g, 10.1 mmol, 3 eq) at 25° C. After 30 min,phenyl carbonochloridate (636.1 mg, 4.06 mmol, 508.9 uL, 1.2 eq) wasadded to the reaction. Then the reaction was stirred at 25° C. for 2 h.Then Intermediate 4 (894.9 mg, 3.39 mmol, 1 eq), TEA (1.71 g, 16.9 mmol,2.36 mL, 5 eq) and DMAP (206.8 mg, 1.69 mmol, 0.5 eq) was added to thereaction. The reaction was stirred at 50° C. for 12 h. LCMS showed thereaction was not completed, but desired Intermediate was detected byLCMS. The reaction was concentrated to give the residue. The residue waspurified by pre-HPLC (column: Phenomenex luna C18 250*50 mm*10 um;mobile phase: [water (0.1% TFA)-ACN]; B %: 10%-40%, 18 min).Intermediate 5 (230.0 mg, 328.7 umol, 9.7% yield, TFA) was obtained as aoff-white solid.

General Procedure for Preparation of Intermediate 6

To a solution of Intermediate 5 (200.0 mg, 285.8 umol, 1 eq, TFA) inMeOH (5.00 mL) was added HCl/dioxane (4 M, 10.0 mL, 139.9 eq), then thereaction was stirred at 25° C. for 2 h. LCMS showed the reaction wascompleted and desired Intermediate was detected by LCMS. The reactionwas concentrated to give the residue without purification. Intermediate6 (160.0 mg, crude, HCl) was obtained as a brown solid.

General Procedure for Preparation of Compound 1

To a solution of Intermediate 6 (140.0 mg, 288.3 umol, 1 eq),prop-2-enoyl chloride (31.3 mg, 346.0 umol, 28.2 uL, 1.2 eq), and TEA(87.5 mg, 865.0 umol, 120.4 uL, 3 eq) in DCM (3.00 mL) are stirred at25° C. for 1 h. LCMS showed the reaction was not completed, but desiredIntermediate was detected by LCMS. The reaction was concentrated to givethe residue. The residue was purified by pre-HPLC (column: Luna C18100*30 5u; mobile phase: [water (0.2% FA)-ACN]; B %: 1%-22%, 15 min).Compound 1 (17.0 mg, 30.4 umol, 10.5% yield, 96.5% purity) was obtainedas a off-white solid.

¹H NMR: DMSO Varian_Y_400 MHz

12.17 (s, 1H), 11.49-11.54 (m, 1H), 11.35 (s, 1H), 9.24 (s, 1H), 8.83(br d, J=7.1 Hz, 1H), 8.12-8.18 (m, 1H), 7.92 (d, J=5.7 Hz, 1H), 7.85(d, J=8.6 Hz, 1H), 7.83-7.88 (m, 1H), 7.58 (d, J=8.8 Hz, 2H), 7.08 (s,1H), 6.28 (br s, 1H), 6.13-6.19 (m, 2H), 5.62-5.69 (m, 1H), 4.71 (br d,J=7.1 Hz, 1H), 4.24 (br s, 2H), 3.87 (br d, J=4.9 Hz, 4H), 3.75 (br d,J=4.6 Hz, 6H)

Example 2 Synthesis of Compound 3

General Procedure for Preparation of Intermediate 2

A mixture of Intermediate 1 (20.0 g, 116.2 mmol, 1 eq), diethylcarbonate (17.8 g, 151.1 mmol, 18.3 mL, 1.3 eq), LDA (2 M, 145.3 mL, 2.5eq) in THE (100.0 mL) was degassed and purged with N₂ for 3 times, andthen the mixture was stirred at −70-25° C. for 4 h under N₂ atmosphere.TLC (Petroleum ether/Ethyl acetate=3/1, R_(f)=0.68) showed the reactionwas completed. The reaction mixture was partitioned between H₂O (100.0mL) and EtOAc (250.0 mL). The organic phase was separated, washed withbrine, dried over Na₂SO₄, filtered and concentrated under reducedpressure to give a residue. The residue was purified by silica gelchromatography eluted with Petroleum ether/Ethyl acetate=3/1 to 0/1.Intermediate 2 (18.0 g, 73.7 mmol, 63.4% yield) was obtained as a yellowliquid.

General Procedure for Preparation of Intermediate 4

A mixture of Intermediate 2 (10.0 g, 40.9 mmol, 1 eq), Intermediate 3(8.21 g, 40.9 mmol, 1 eq), K₂CO₃ (5.66 g, 40.9 mmol, 1 eq) in DMF (50.0mL) was degassed and purged with N₂ for 3 times, and then the mixturewas stirred at 120° C. for 16 h under N₂ atmosphere. TLC (Petroleumether/Ethyl acetate=0/1, R_(f)=0.79) showed the reaction was completed.The reaction mixture was partitioned between H₂O (100.0 mL) and EtOAc(500.0 mL). The organic phase was separated, washed with brine, driedover Na₂SO₄, filtered and concentrated under reduced pressure to give aresidue. The residue was purified by silica gel chromatography elutedwith Petroleum ether/Ethyl acetate=0/1. Intermediate 4 (10.0 g, 27.5mmol, 67.1% yield) was obtained as a brown oil.

¹H NMR: CDCl₃ 400 MHz

8.17 (d, J=6.1 Hz, 1H), 6.66 (d, J=2.3 Hz, 1H), 6.59 (dd, J=2.3, 5.9 Hz,1H), 4.70 (br d, J=5.7 Hz, 1H), 4.16 (q, J=7.1 Hz, 2H), 3.68 (s, 2H),3.41 (br d, J=11.6 Hz, 1H), 3.08-3.20 (m, 1H), 3.02 (br dd, J=7.5, 11.5Hz, 1H), 2.11 (br s, 1H), 1.91 (br d, J=4.4 Hz, 1H), 1.71-1.80 (m, 1H),1.64 (dtd, J=4.2, 8.8, 13.2 Hz, 1H), 1.47-1.56 (m, 2H), 1.43 (br s, 9H),1.21-1.27 (m, 3H)

General Procedure for Preparation of Intermediate 5

To a solution of Intermediate 4 (5.00 g, 13.7 mmol, 1 eq) in EtOAc (25mL) was added HCl/EtOAc (4 M, 376.9 uL). The mixture was stirred at 25°C. for 1 h. TLC (Dichloromethane/Methanol=10/1, R_(f)=0.03) showed thereaction was completed. The reaction mixture was concentrated underreduced pressure to remove EtOAc. The residue was diluted with H₂O (50.0mL) and extracted with EtOAc (50.0 mL×3). The combined organic layerswere washed with brine, dried over Na₂SO₄, filtered and concentratedunder reduced pressure to give a residue without purification.Intermediate 5 (4.00 g, crude) was obtained as a brown solid.

¹H NMR: MeOD 400 MHz

8.18 (d, J=7.3 Hz, 1H), 7.27 (d, J=2.8 Hz, 1H), 7.20 (dd, J=3.0, 7.4 Hz,1H), 4.27-4.34 (m, 1H), 4.23 (q, J=7.1 Hz, 2H), 3.99 (s, 2H), 3.42-3.50(m, 2H), 2.23 (td, J=4.1, 8.3 Hz, 1H), 1.94-1.99 (m, 1H), 1.73-1.86 (m,2H), 1.29 (t, J=7.1 Hz, 3H), 1.24 (t, J=7.2 Hz, 2H)

General Procedure for Preparation of Intermediate 6

To a solution of ethyl Intermediate 5 (2.00 g, 7.59 mmol, 1 eq) in DCM(14.0 mL) was added TEA (1.54 g, 15.19 mmol, 2.11 mL, 2 eq), but-2-ynoicacid (638.5 mg, 7.59 mmol, 1 eq) and HATU (3.00 g, 7.90 mmol, 1.04 eq).The mixture was stirred at 25° C. for 4 h. TLC(Dichloromethane:Methanol=10:1, R_(f)=0.55) showed the reaction wascompleted. The reaction mixture was partitioned between H₂O (10.0 mL)and EtOAc (30.0 mL). The organic phase was separated, washed with brine,dried over Na₂SO₄, filtered and concentrated under reduced pressure togive a residue without purification. Intermediate 6 (1.50 g, crude) wasobtained as a brown gum.

¹H NMR: DMSO 400 MHz

8.74-8.69 (m, 1H), 8.23 (d, J=7.3 Hz, 1H), 7.20 (br s, 1H), 7.08 (br d,J=5.7 Hz, 1H), 4.15 (q, J=7.1 Hz, 2H), 3.93 (s, 2H), 3.69-3.80 (m, 1H),3.33 (br d, J=9.3 Hz, 2H), 3.07-3.12 (m, 2H), 1.95 (s, 3H), 1.80-1.90(m, 2H), 1.46-1.64 (m, 2H), 1.22 (t, J=7.2 Hz, 3H)

General Procedure for Preparation of Intermediate 7

To a solution of Intermediate 6 (0.50 g, 1.52 mmol, 1 eq) in THE (3.00mL) was added LiOH·H₂O (191.1 mg, 4.55 mmol, 3 eq) in H₂O (3.00 mL). Themixture was stirred at 25° C. for 3 h. TLC(Dichloromethane/Methanol=10/1, R_(f)=0) showed the reaction wascompleted. The reaction mixture was partitioned between EtOAc (30.0 mL)and H₂O (10.0 mL). The organic phase was separated, washed with brine,dried over Na₂SO₄, filtered and concentrated under reduced pressure togive a residue without purification. Intermediate 7 (0.50 g, crude) wasobtained as a brown gum.

General Procedure for Preparation of Compound 3

To a solution of Intermediate 7 (0.40 g, 1.33 mmol, 1 eq) in DMF (10.0mL) was added Intermediate 3A (392.0 mg, 1.33 mmol, 1 eq), HATU (757.0mg, 1.99 mmol, 1.5 eq) and Pyridine (524.9 mg, 6.64 mmol, 535.7 uL, 5eq). The mixture was stirred at 25° C. for 10 h. LCMS showed thereaction was completed. The mixture was poured into H₂O (30.0 mL), thenwas filtered and filter cake was concentrated in vacuum. The residue waspurified by prep-HPLC column: Phenomenex Luna C18 200*40 mm*10 um;mobile phase: [water (0.05% HCl)-ACN]; B %: 10%-30%, 10 min. GiveCompound 3 (106.0 mg, 179.8 umol, 13.5% yield, 98.2% purity) as a yellowsolid.

¹H NMR: DMSO 400 MHz

13.56 (br d, J=3.7 Hz, 1H), 12.89 (br s, 1H), 10.75 (br s, 1H), 8.73 (d,J=7.1 Hz, 1H), 8.31 (s, 1H), 8.21-8.27 (m, 1H), 7.91 (d, J=8.6 Hz, 2H),7.71 (d, J=8.8 Hz, 2H), 7.33 (br s, 1H), 7.25 (br s, 1H), 7.09 (br s,1H), 4.01 (s, 2H), 3.94-3.99 (m, 6H), 3.78-3.83 (m, 5H), 3.72-3.77 (m,2H), 1.95 (s, 3H), 1.87 (br s, 2H), 1.51-1.63 (m, 2H)

General Procedure for Preparation of Intermediate 3A

General Procedure for Preparation of Intermediate 3

To a solution of Intermediate 1 (50.0 g, 325.5 mmol, 1 eq), sodium;2-methylpropan-2-olate (32.8 g, 341.8 mmol, 1.05 eq) in THE (350.0 mL)was added dropwise Intermediate 2 (62.6 g, 354.8 mmol, 45.4 mL, 1.09 eq)at 10° C. The mixture was stirred at 25° C. for 2 h. TLC (Petroleumether/Ethyl acetate=1/1, R_(f)=0.59) showed the reaction was completed.The reaction mixture was added H₂O (100.0 mL), filtered and the filtercake was washed with MeOH (50.0 mL×3), concentrated in vacuum. Theresidue was used for the next step without purification. GiveIntermediate 3 (80.0 g, 272.3 mmol, 83.6% yield) as a white solid.

¹H NMR. DMSO 400 MHz

8.79-8.85 (m, 1H), 8.11-8.20 (m, 3H), 7.74-7.81 (m, 1H), 7.64-7.72 (m,2H), 6.97 (d, J=4.0 Hz, 1H)

General Procedure for Preparation of Intermediate 4

To a solution of Intermediate 3 (50.0 g, 170.2 mmol, 1 eq) in THE (300.0mL) was added drop wise LDA (2 M, 127.6 mL, 1.5 eq) at −78° C. Then themixture was stirred at −78° C. for 1 h. Then I₂ (56.1 g, 221.2 mmol,44.5 mL, 1.3 eq) in THE (100.0 mL) was added to the mixture. The mixturewas stirred at −78° C. for 1 h. TLC (Petroleum ether/Ethyl acetate=1/1,R_(f)=0.71) showed the reaction was completed. HCl (1M, 200.0 mL) wasadded to the mixture. Then the mixture was concentrated in vacuum toremove THF. The residue was diluted with H₂O (100.0 mL), extracted withEtOAc (300.0 mL×3). The combined organic layers were washed with brine(500.0 mL), dried over Na₂SO₄, concentrated in vacuum. The crude productwas triturated with MeCN (200.0 mL) at 25° C. for 2 h. Give Intermediate4 (50.0 g, 119.1 mmol, 70.0% yield) as a off-white solid.

¹H NMR. DMSO 400 MHz

8.75-8.79 (m, 1H), 8.08-8.14 (m, 2H), 7.75-7.82 (m, 1H), 7.65-7.73 (m,2H), 7.38 (s, 1H)

General Procedure for Preparation of Intermediate 1A

To a solution of Intermediate 4 (70.0 g, 166.8 mmol, 1 eq) in THF (400.0mL) was added NaOH/MeOH (5 M, 237.8 mL, 7.13 eq). Then the mixture wasstirred at 25° C. for 1 h. TLC (Petroleum ether/Ethyl acetate=0/1,R_(f)=0.62) showed the reaction was completed. The reaction mixture wasconcentrated under reduced pressure to remove THE and MeOH. The residuewas diluted with NH₄Cl (aq, 500.0 mL), filtered and the filter cake wasconcentrated under reduced pressure to give a residue. The crude productwas triturated with MeCN (50.0 mL) at 25° C. for 2 h. Give Intermediate1A (40.0 g, 143.1 mmol, 85.8% yield) as a brown solid.

¹H NMR: DMSO 400 MHz

13.14 (br s, 1H), 8.47-8.59 (m, 1H), 6.89 (s, 1H)

General Procedure for Preparation of Intermediate 2A

A mixture of Intermediate 1A (40.0 g, 143.1 mmol, 1 eq), morpholine(24.9 g, 286.2 mmol, 25.1 mL, 2 eq) in n-butanol (200.0 mL) was degassedand purged with N₂ for 3 times, and then the mixture was stirred at 100°C. for 12 h under N₂ atmosphere. TLC (Dichloromethane/Methanol=10/1,R_(f)=0.62) showed the reaction was completed. The reaction mixture wasfiltered and the filter cake was concentrated. The crude product wasused for the next step without purification. Give Intermediate 2A (40.0g, 121.1 mmol, 84.6% yield) as a brown solid

¹H NMR: DMSO 400 MHz

12.27 (br s, 1H), 8.08 (s, 1H), 6.88 (s, 1H), 3.77-3.82 (m, 4H),3.67-3.72 (m, 4H)

General Procedure for Preparation of Intermediate 3A

A solution of Intermediate 2A (20.0 g, 60.5 mmol, 1 eq),(4-aminophenyl)boronic acid (15.7 g, 90.8 mmol, 1.5 eq, HCl), K₂CO₃(50.2 g, 363.5 mmol, 6 eq) in dioxane (100.0 mL) and H₂O (25.0 mL) wasstirred at 25° C. for 0.5 h. Then Pd(dppf)Cl₂ (4.43 g, 6.06 mmol, 0.1eq) was added. The mixture was stirred at 100° C. for 12 h. TLC(Dichloromethane/Methanol=10/1, R_(f)=0.47) showed the reaction wascompleted. The reaction mixture was concentrated under reduced pressureto remove dioxane. The residue was diluted with H₂O (150.0 mL) andextracted with EtOAc (300.0 mL×5). The combined organic layers werewashed with brine (300.0 mL), dried over Na₂SO₄, filtered andconcentrated under reduced pressure to give a residue. The crude productwas triturated with MeOH (60.0 mL) for 2 h at 25° C. Give Intermediate3A (8.50 g, 28.7 mmol, 47.5% yield) as a brown solid

¹H NMR. DMSO 400 MHz

11.92 (br s, 1H), 8.12 (s, 1H), 7.57 (br d, J=8.4 Hz, 3H), 6.83 (s, 1H),6.59 (br d, J=8.4 Hz, 2H), 5.32 (s, 2H), 3.83 (br d, J=4.6 Hz, 4H), 3.74(br d, J=4.6 Hz, 4H)

Example 3 Synthesis of Compound 4

General Procedure for Preparation of Intermediate 2

To a Intermediate 3A (1.50 g, 5.08 mmol, 1 eq), Intermediate 1 (920.0mg, 5.08 mmol, 1 eq), BOP (2.25 g, 5.08 mmol, 1 eq) in DMF (10.0 mL) wasadded TEA (3.60 g, 35.5 mmol, 4.95 mL, 7 eq). The mixture was stirred at25° C. for 12 h. LCMS showed the reaction was complete. The mixture waspoured into H₂O (30.0 mL), filtered and filter cake was concentrated invacuum. The crude product was used for the next step withoutpurification. Give the Intermediate 2 (2.80 g, crude) as a yellow solid.

¹H NMR. DMSO 400 MHz

12.17 (br s, 1H), 10.39 (br s, 1H), 8.12-8.26 (m, 3H), 7.86 (br d,J=7.94 Hz, 2H), 7.64 (br t, J=9.70 Hz, 4H), 7.10 (br s, 1H), 3.86 (br s,6H), 3.74 (br s, 4H)

General Procedure for Preparation of Intermediate 3

To a solution of SnCl₂·2H₂O (2.95 g, 13.0 mmol, 6 eq) in HCl (1.2 M,10.0 mL, 5.5 eq) was added Intermediate 2 (1.00 g, 2.18 mmol, 1 eq) andEtOH (3.00 mL), the mixture was stirred at 60° C. for 24 h. LCMS showedthe reaction was complete. The reaction mixture was concentrated underreduced pressure to remove EtOH. The residue was diluted with H₂O (20.0mL) and added a.q. NaHCO₃ to adjust pH=8. Then the mixture was filteredand filter cake was concentrated in vacuum. The crude product was usedfor the next step without purification. Give Intermediate 3 (0.52 g,1.21 mmol, 55.6% yield) as a yellow solid.

General Procedure for Preparation of Compound 4

To a solution of Intermediate 3 (0.50 g, 1.17 mmol, 1 eq) in DMF (10.0mL) was added TEA (236.1 mg, 2.33 mmol, 324.8 uL, 2 eq) and prop-2-enoylchloride (105.6 mg, 1.17 mmol, 95.1 uL, 1 eq). Then the mixture wasstirred at 20° C. for 12 h. LCMS showed the reaction was complete. Themixture was poured into H₂O (30.0 mL), filtered and filter cake wasconcentrated in vacuum. The crude product was purified by reversed-phaseHPLC (column: Luna C18 100*30 5u; mobile phase: [water (0.04% HCl)-ACN];B %: 10%-32%, 11 min). Give the Compound 4 (53.0 mg, 101.7 umol, 8.72%yield, 99.6% purity, HCl) as a yellow solid.

¹H NMR: DMSO 400 MHz

13.06 (br s, 1H), 10.42 (s, 1H), 10.19 (s, 1H), 8.34 (s, 1H), 7.89 (d,J=8.60 Hz, 2H), 7.72 (d, J=8.82 Hz, 2H), 7.63 (d, J=8.60 Hz, 2H), 7.38(s, 1H), 7.30 (d, J=8.38 Hz, 2H), 6.45 (dd, J=16.98, 10.14 Hz, 1H), 6.24(dd, J=16.98, 1.76 Hz, 1H), 5.74 (dd, J=10.03, 1.87 Hz, 1H), 3.99 (br t,J=4.41 Hz, 4H), 3.81 (br t, J=4.41 Hz, 4H), 3.63 (s, 2H)

Example 4 Synthesis of Compound 5

General Procedure for Preparation of Intermediate 2

To a Intermediate 3A (1.50 g, 5.08 mmol, 1 eq), Intermediate 1 (920.0mg, 5.08 mmol, 1 eq), BOP (2.25 g, 5.08 mmol, 1 eq) in DMF (10.0 mL) wasadded TEA (3.60 g, 35.5 mmol, 4.95 mL, 7 eq). The mixture was stirred at25° C. for 12 h. LCMS showed the reaction was complete. The mixture waspoured into H₂O (30.0 mL), filtered and filter cake was concentrated invacuum. The crude product was used for the next step withoutpurification. Give the Intermediate 2 (2.80 g, crude) as a yellow solid.

¹H NMR. DMSO 400 MHz

12.17 (br s, 1H), 10.39 (br s, 1H), 8.12-8.26 (m, 3H), 7.86 (br d,J=7.94 Hz, 2H), 7.64 (br t, J=9.70 Hz, 4H), 7.10 (br s, 1H), 3.86 (br s,6H), 3.74 (br s, 4H)

General Procedure for Preparation of Intermediate 3

To a solution of SnCl₂·2H₂O (2.95 g, 13.0 mmol, 6 eq) in HCl (1.2 M,10.0 mL, 5.5 eq) was added Intermediate 2 (1.00 g, 2.18 mmol, 1 eq) andEtOH (3.00 mL), the mixture was stirred at 60° C. for 24 h. LCMS showedthe reaction was complete. The reaction mixture was concentrated underreduced pressure to remove EtOH. The residue was diluted with H₂O (20.0mL) and added a.q. NaHCO₃ to adjust pH=8. Then the mixture was filteredand filter cake was concentrated in vacuum. The crude product was usedfor the next step without purification. Give Intermediate 3 (0.52 g,1.21 mmol, 55.6% yield) as a yellow solid.

General Procedure for Preparation of Compound 5

To a solution of Intermediate 3 (0.20 g, 466.7 umol, 1 eq),(E)-4-(dimethylamino)but-2-enoic acid (77.3 mg, 466.7 umol, 1 eq, HCl),TEA (330.6 mg, 3.27 mmol, 454.7 uL, 7 eq) in DMF (10.0 mL) was addedHATU (266.2 mg, 700.1 umol, 1.5 eq). The mixture was stirred at 25° C.for 12 h. LCMS showed the reaction was completed. The mixture was pouredinto H₂O (30.0 mL), then filtered and filter cake was concentrated invacuum. The crude product was purified by reversed-phase HPLC (column:Luna C18 100*30 5u; mobile phase: [water (0.04% HCl)-ACN]; B %: 1%-25%,11 min). Give the Compound 5 (31.0 mg, 53.1 umol, 11.4% yield, 98.8%purity, HCl) as a yellow solid.

¹H NMR: DMSO 400 MHz

13.22 (br s, 1H), 10.80 (br s, 1H), 10.51 (d, J=19.85 Hz, 2H), 8.36 (s,1H), 7.90 (d, J=8.60 Hz, 2H), 7.74 (d, J=8.60 Hz, 2H), 7.65 (d, J=8.60Hz, 2H), 7.42 (s, 1H), 7.31 (d, J=8.60 Hz, 2H), 6.73-6.85 (m, 1H), 6.50(d, J=15.21 Hz, 1H), 3.99-4.04 (m, 4H), 3.89-3.94 (m, 2H), 3.79-3.85 (m,5H), 3.65 (br s, 1H), 2.75 (d, J=4.63 Hz, 6H)

Example 5 Synthesis of Compound 6

General Procedure for Preparation of Intermediate 3

To a solution of Intermediate 1 (5.00 g, 31.5 mmol, 1 eq), Intermediate2 (12.6 g, 63.0 mmol, 2 eq) in EtOH (30.0 mL) was added TEA (6.38 g,63.0 mmol, 8.78 mL, 2 eq). The mixture was stirred at 75° C. for 8 h.TLC (Petroleum ether/Ethyl acetate=3/1, R_(f)=0.22) showed the reactionwas completed. The reaction mixture was concentrated under reducedpressure to remove EtOH. The residue was diluted with H₂O (30.0 mL) andextracted with EtOAc (30.0 mL×3). The combined organic layers werewashed with brine (50.0 mL), dried over Na₂SO₄, filtered andconcentrated under reduced pressure to give a residue. The residue waspurified by column chromatography (SiO₂, Petroleum ether/Ethylacetate=50/1 to 0/1). Give Intermediate 3 (8.00 g, 24.8 mmol, 78.6%yield) as a yellow solid.

¹H NMR: CDCl₃ 400 MHz

8.20 (d, J=5.9 Hz, 1H), 7.58 (d, J=2.4 Hz, 1H), 6.94 (br d, J=3.5 Hz,1H), 4.57 (br s, 1H), 3.86 (br d, J=12.3 Hz, 1H), 3.57-3.74 (m, 2H),3.14-3.33 (m, 2H), 2.02-1.98 (m, 1H), 1.77-1.90 (m, 1H), 1.64-1.71 (m,1H), 1.52-1.61 (m, 1H), 1.44 (br s, 9H)

General Procedure for Preparation of Intermediate 4

To a solution of Intermediate 3 (7.00 g, 21.71 mmol, 1 eq) in EtOAc(25.0 mL) was added HCl/EtOAc (4 M, 70.0 mL, 12.8 eq). The mixture wasstirred at 25° C. for 3 h. TLC (Petroleum ether/Ethyl acetate=3/1,R_(f)=0.02) showed the reaction was completed. The reaction mixture wasfiltered and the filter cake was concentrated in vacuum. The residue wasused for the next step without purification. Give Intermediate 4 (4.00g, 15.4 mmol, 71.2% yield, HCl) as a yellow solid.

General Procedure for Preparation of Intermediate 5

To a solution of Intermediate 4 (4.00 g, 15.4 mmol, 1 eq, HCl),but-2-ynoic acid (1.30 g, 15.4 mmol, 1 eq) and BOP (6.84 g, 15.4 mmol, 1eq) in DMF (20.0 mL) was added TEA (9.39 g, 92.7 mmol, 12.9 mL, 6 eq).The mixture was stirred at 25° C. for 4 h. TLC (Petroleum ether/Ethylacetate=0/1, R_(f)=0.43) showed the reaction was completed. The reactionmixture was poured into water (100.0 mL) and extracted with EtOAc (60.0mL×3). The combined organic layers were washed with brine (50.0 mL×3),dried over Na₂SO₄, filtered and concentrated under reduced pressure togive a residue. The residue was purified by column chromatography (SiO₂,Petroleum ether/Ethyl acetate=50/1 to 1/1). Give Intermediate 5 (3.50 g,12.1 mmol, 78.5% yield) as a yellow solid.

¹H NMR: DMSO 400 MHz

8.63 (br d, J=7.1 Hz, 1H), 8.14 (d, J=6.0 Hz, 1H), 7.56 (d, J=2.4 Hz,1H), 7.16 (dd, J=2.6, 6.0 Hz, 1H), 3.78-3.91 (m, 2H), 3.61-3.76 (m, 1H),3.10-3.30 (m, 1H), 3.02 (dd, J=9.2, 13.0 Hz, 1H), 1.93-1.99 (m, 3H),1.72-1.91 (m, 2H), 1.43-1.60 (m, 2H)

General Procedure for Preparation of Intermediate 5a

To a solution of Intermediate 5 (3.00 g, 10.4 mmol, 1 eq) in EtOH (10.0mL) and H₂O (10.0 mL) was added Fe (2.91 g, 52.0 mmol, 5 eq) and NH₄Cl(2.78 g, 52.0 mmol, 5 eq). The mixture was stirred at 80° C. for 10 h.TLC (Petroleum ether/Ethyl acetate=0/1, R_(f)=0.05) showed the reactionwas completed. The reaction mixture was filtered and the filter wasconcentrated. The residue was based to pH=8, extracted with EtOAc (100.0mL×3). The combined organic layers were washed with brine (50.0 mL),dried over Na₂SO₄, filtered and concentrated under reduced pressure togive a residue. The crude product was used for the next step withoutpurification. Give Intermediate 5a (2.00 g, 7.74 mmol, 74.4% yield) as abrown solid.

¹H NMR: DMSO 400 MHz

8.54 (br d, J=7.2 Hz, 1H), 7.53-7.59 (m, 1H), 6.06-6.13 (m, 1H), 5.82(d, J=2.2 Hz, 1H), 5.50 (s, 2H), 3.67-3.53 (m, 3H), 2.72-2.81 (m, 1H),2.68-2.59 (m, 1H), 1.95 (s, 3H), 1.77-1.84 (m, 1H), 1.67-1.75 (m, 1H),1.39-1.51 (m, 2H)

General Procedure for Preparation of Intermediate 6

To a solution of Intermediate 5a (0.20 g, 677.1 umol, 1 eq), K₂CO₃(280.7 mg, 2.03 mmol, 3 eq) in THF (5.00 mL) was added phenylcarbonochloridate (106.0 mg, 677.1 umol, 84.8 uL, 1 eq), then themixture was stirred at 25° C. for 2 h. LCMS showed the reaction wascompleted. The reaction mixture was used for the next step in solventTHF without work-up. Give Intermediate 6 (281.0 mg, crude) in brownsolvent THF was used for the next step.

General Procedure for Preparation of Compound 6

To a solution of Intermediate 6 (0.28 g, 673.9 umol, 1 eq), Intermediate3A (156.6 mg, 606.5 umol, 0.9 eq), DMAP (8.23 mg, 67.4 umol, 0.1 eq) inTHF (1.00 mL) was added TEA (409.2 mg, 4.04 mmol, 562.8 uL, 6 eq). Themixture was stirred at 70° C. for 10 h. LCMS showed the reaction wascompleted. The reaction mixture was filtered and the filter wasconcentrated to give a residue. The residue was purified by prep-HPLC(column: Luna C18 100*30 5u; mobile phase: [water (0.04% HCl)-ACN]; B %:10%-30%, 11 min). Give Compound 6 (40.0 mg, 64.9 umol, 9.63% yield, HCl,95.9% purity) as a off-white solid.

¹H NMR: DMSO 400 MHz

13.32 (br s, 1H), 11.21 (br s, 1H), 10.33 (br s, 1H), 8.70 (br d, J=7.3Hz, 1H), 8.33 (s, 1H), 7.93 (br d, J=8.4 Hz, 2H), 7.84 (br d, J=7.5 Hz,1H), 7.56 (br d, J=8.4 Hz, 2H), 7.43 (s, 1H), 6.86 (br s, 1H), 6.50 (brs, 1H), 4.02 (br s, 4H), 3.80 (br s, 4H), 3.74-3.76 (m, 3H), 3.13-3.31(m, 2H), 1.92 (s, 3H), 1.83 (br s, 2H), 1.46-1.62 (m, 2H)

Example 6 Synthesis of Compound 7

General Procedure for Preparation of Intermediate 2

To a solution of Intermediate 2A (2.00 g, 6.06 mmol, 1 eq), Intermediate1 (1.64 g, 9.09 mmol, 1.5 eq), K₂CO₃ (5.02 g, 36.3 mmol, 6 eq) indioxane (12.0 mL) and H₂O (3.00 mL) was added Pd(dppf)Cl₂ (443.2 mg,605.8 umol, 0.1 eq). The mixture was stirred at 100° C. for 12 h. TLC(Dichloromethane/Methanol=10/1, R_(f)=0.05) showed the reaction wascompleted. The reaction mixture was concentrated in vacuum. The residuewas diluted with H₂O (20.0 mL), and extracted with EtOAc (30.0 mL×3).The aqueous phase was acidized by HCl (0.50 M, 20.0 mL). Theprecipitation was filtered and concentrated in vacuum. The residue wasused for the next step without purification. Give Intermediate 2 (1.10g, 3.25 mmol, 53.6% yield) as a brown solid.

¹H NMR: DMSO 400 MHz

12.98 (br s, 1H), 8.34 (s, 1H), 7.90 (br d, J=7.5 Hz, 2H), 7.33-7.45 (m,3H), 3.99 (br s, 4H), 3.82 (br s, 4H), 3.63 (br s, 2H)

General Procedure for Preparation of Compound 7

To a solution of Intermediate 2 (0.20 g, 591.0 umol, 1 eq), Intermediate5a (158.8 mg, 614.7 umol, 1.04 eq), TEA (119.6 mg, 1.18 mmol, 164.5 uL,2 eq) in DMF (5.00 mL) was added HATU (233.7 mg, 614.7 umol, 1.04 eq).The mixture was stirred at 25° C. for 5 h. LCMS showed the reaction wascompleted. The reaction mixture was diluted with EtOAc (20.0 mL),filtered and the filter was washed with H₂O (10.0 mL×3) and brine (20.0mL), dried over Na₂SO₄, concentrated in vacuum. The residue was purifiedby prep-HPLC (column: Luna C18 100*30 5u; mobile phase: [water (0.04%HCl)-ACN]; B %: %-%, 11 min). Give Compound 7 (50.0 mg, 86.4 umol, 14.6%yield, 92.5% purity) as a yellow solid.

¹H NMR: DMSO 400 MHz

13.46 (br s, 1H), 13.09 (br s, 1H), 12.55-12.94 (m, 1H), 8.75 (br d,J=7.3 Hz, 1H), 8.38 (s, 1H), 7.98 (d, J=8.4 Hz, 2H), 7.89 (d, J=7.5 Hz,1H), 7.49-7.56 (m, 3H), 7.10-6.82 (m, 2H), 4.04-4.09 (m, 4H), 3.92 (s,2H), 3.81-3.86 (m, 5H), 3.70-3.80 (m, 2H), 3.15-3.34 (m, 2H), 1.95 (s,3H), 1.86 (br s, 2H), 1.48-1.65 (m, 2H)

General Procedure for Preparation of Intermediate 3

To a solution of Intermediate 1 (5.00 g, 31.5 mmol, 1 eq), Intermediate2 (12.6 g, 63.0 mmol, 2 eq) in EtOH (30.0 mL) was added TEA (6.38 g,63.0 mmol, 8.78 mL, 2 eq). The mixture was stirred at 75° C. for 8 h.TLC (Petroleum ether/Ethyl acetate=3/1, R_(f)=0.22) showed the reactionwas completed. The reaction mixture was concentrated under reducedpressure to remove EtOH. The residue was diluted with H₂O (30.0 mL) andextracted with EtOAc (30.0 mL×3). The combined organic layers werewashed with brine (50.0 mL), dried over Na₂SO₄, filtered andconcentrated under reduced pressure to give a residue. The residue waspurified by column chromatography (SiO₂, Petroleum ether/Ethylacetate=50/1 to 0/1). Give Intermediate 3 (8.00 g, 24.8 mmol, 78.6%yield) as a yellow solid.

¹H NMR: CDCl₃ 400 MHz

8.20 (d, J=5.9 Hz, 1H), 7.58 (d, J=2.4 Hz, 1H), 6.94 (br d, J=3.5 Hz,1H), 4.57 (br s, 1H), 3.86 (br d, J=12.3 Hz, 1H), 3.57-3.74 (m, 2H),3.14-3.33 (m, 2H), 2.02-1.98 (m, 1H), 1.77-1.90 (m, 1H), 1.64-1.71 (m,1H), 1.52-1.61 (m, 1H), 1.44 (br s, 9H)

General Procedure for Preparation of Intermediate 4

To a solution of Intermediate 3 (7.00 g, 21.71 mmol, 1 eq) in EtOAc(25.0 mL) was added HCl/EtOAc (4 M, 70.0 mL, 12.8 eq). The mixture wasstirred at 25° C. for 3 h. TLC (Petroleum ether/Ethyl acetate=3/1,R_(f)=0.02) showed the reaction was completed. The reaction mixture wasfiltered and the filter cake was concentrated in vacuum. The residue wasused for the next step without purification. Give Intermediate 4 (4.00g, 15.4 mmol, 71.2% yield, HCl) as a yellow solid.

General Procedure for Preparation of Intermediate 5

To a solution of Intermediate 4 (4.00 g, 15.4 mmol, 1 eq, HCl),but-2-ynoic acid (1.30 g, 15.4 mmol, 1 eq) and BOP (6.84 g, 15.4 mmol, 1eq) in DMF (20.0 mL) was added TEA (9.39 g, 92.7 mmol, 12.9 mL, 6 eq).The mixture was stirred at 25° C. for 4 h. TLC (Petroleum ether/Ethylacetate=0/1, R_(f)=0.43) showed the reaction was completed. The reactionmixture was poured into water (100.0 mL) and extracted with EtOAc (60mL×3). The combined organic layers were washed with brine (50.0 mL×3),dried over Na₂SO₄, filtered and concentrated under reduced pressure togive a residue. The residue was purified by column chromatography (SiO₂,Petroleum ether/Ethyl acetate=50/1 to 1/1). Give Intermediate 5 (3.50 g,12.1 mmol, 78.5% yield) as a yellow solid.

¹H NMR: DMSO 400 MHz

8.63 (br d, J=7.1 Hz, 1H), 8.14 (d, J=6.0 Hz, 1H), 7.56 (d, J=2.4 Hz,1H), 7.16 (dd, J=2.6, 6.0 Hz, 1H), 3.78-3.91 (m, 2H), 3.61-3.76 (m, 1H),3.10-3.30 (m, 1H), 3.02 (dd, J=9.2, 13.0 Hz, 1H), 1.93-1.99 (m, 3H),1.72-1.91 (m, 2H), 1.43-1.60 (m, 2H)

General Procedure for Preparation of Intermediate 5a

To a solution of Intermediate 5 (3.00 g, 10.4 mmol, 1 eq) in EtOH (10.0mL) and H₂O (10.0 mL) was added Fe (2.91 g, 52.0 mmol, 5 eq) and NH₄Cl(2.78 g, 52.0 mmol, 5 eq). The mixture was stirred at 80° C. for 10 h.TLC (Petroleum ether/Ethyl acetate=0/1, R_(f)=0.05) showed the reactionwas completed. The reaction mixture was filtered and the filter wasconcentrated. The residue was based to pH=8, extracted with EtOAc (100.0mL×3). The combined organic layers were washed with brine (50.0 mL),dried over Na₂SO₄, filtered and concentrated under reduced pressure togive a residue. The crude product was used for the next step withoutpurification. Give Intermediate 5a (2.00 g, 7.74 mmol, 74.4% yield) as abrown solid.

¹H NMR: DMSO 400 MHz

8.54 (br d, J=7.2 Hz, 1H), 7.53-7.59 (m, 1H), 6.06-6.13 (m, 1H), 5.82(d, J=2.2 Hz, 1H), 5.50 (s, 2H), 3.53-3.67 (m, 3H), 2.72-2.81 (m, 1H),2.59-2.68 (m, 1H), 1.95 (s, 3H), 1.77-1.84 (m, 1H), 1.67-1.75 (m, 1H),1.39-1.51 (m, 2H)

Example 7 Synthesis of Compound 8

General Procedure for Preparation of Intermediate 2

To a solution of Intermediate 3A (1.50 g, 5.08 mmol, 1 eq) in DMSO (15.0mL) was added Intermediate 1 (2.39 g, 10.1 mmol, 2 eq), Pyridine (803.4mg, 10.1 mmol, 819.8 uL, 2 eq). Then the mixture was stirred at 80° C.for 12 h. LC-MS showed the starting material was remained. One new peakwas shown on LC-MS and desired Intermediate was detected. The mixturewas poured into H₂O (50.0 mL), then filtered and filter cake wasconcentrated in vacuum. The crude for next step without purification.Give the Intermediate 2 (2.50 g, crude) as a yellow solid

General Procedure for Preparation of Intermediate 3

To a solution of SnCl₂·2H₂O (5.48 g, 24.2 mmol, 8 eq) in HCl (1.20 M,13.9 mL, 5.5 eq) was added Intermediate 2 (1.50 g, 3.03 mmol, 1 eq) andEtOH (5.00 mL). The mixture was stirred at 80° C. for 12 h. LCMS showedthe reaction was completed. The reaction mixture was concentrated underreduced pressure to remove EtOH. The residue was diluted with H₂O (40.0mL) and added aq. NaHCO₃ to adjust pH=8. Then the mixture was filteredand filter cake was concentrated in vacuum. The crude for next stepwithout purification. Give the Intermediate 3 (1.50 g, crude) as ayellow solid

General Procedure for Preparation of Compound 8

To a solution of Intermediate 3 (0.50 g, 1.08 mmol, 1 eq) in DMSO (10.0mL) was added Pyridine (170.2 mg, 2.15 mmol, 173.7 uL, 2 eq) andprop-2-enoyl chloride (97.4 mg, 1.08 mmol, 87.7 uL, 1 eq). Then themixture was stirred at 20° C. for 12 h. LCMS showed the reaction wascomplete. The mixture was poured into H₂O (50.0 mL), then filtered andfilter cake was concentrated in vacuum. The crude product was purifiedby reversed-phase HPLC (column: Phenomenex Luna C18 200*40 mm*10 um;mobile phase: [water (0.05% HCl)-ACN]; B %: 15%-35%, 10 min). GiveIntermediate Compound 8 (36.0 mg, 64.3 umol, 5.98% yield, 99.2% purity,HCl) as a yellow solid.

¹H NMR: DMSO 400 MHz

12.83-12.97 (m, 1H), 12.83-12.97 (m, 1H), 10.24 (s, 1H), 9.98 (s, 1H),8.31 (s, 1H), 7.88 (d, J=8.60 Hz, 2H), 7.63 (d, J=8.60 Hz, 2H), 7.32 (brs, 1H), 7.21 (dd, J=16.87, 8.71 Hz, 4H), 6.38-6.47 (m, 1H), 6.23 (dd,J=17.09, 1.87 Hz, 1H), 5.71-5.77 (m, 1H), 4.45 (s, 2H), 3.91-3.98 (m,4H), 3.76-3.83 (m, 4H)

Example 8 Synthesis of Compound 9

General Procedure for Preparation of Intermediate 2

To a solution of Intermediate 3A (1.50 g, 5.08 mmol, 1 eq) in DMSO (15.0mL) was added Intermediate 1 (2.39 g, 10.1 mmol, 2 eq), Pyridine (803.4mg, 10.1 mmol, 819.8 uL, 2 eq). Then the mixture was stirred at 80° C.for 12 h. LC-MS showed the starting material was remained. One new peakwas shown on LC-MS and desired Intermediate was detected. The mixturewas poured into H₂O (50.0 mL), then filtered and filter cake wasconcentrated in vacuum. The crude for next step without purification.Give the Intermediate 2 (2.50 g, crude) as a yellow solid

General Procedure for Preparation of Intermediate 3

To a solution of SnCl₂·2H₂O (5.48 g, 24.2 mmol, 8 eq) in HCl (1.20 M,13.9 mL, 5.5 eq) was added Intermediate 2 (1.50 g, 3.03 mmol, 1 eq) andEtOH (5.00 mL). The mixture was stirred at 80° C. for 12 h. LCMS showedthe reaction was completed. The reaction mixture was concentrated underreduced pressure to remove EtOH. The residue was diluted with H₂O (40.0mL) and added aq. NaHCO₃ to adjust pH=8. Then the mixture was filteredand filter cake was concentrated in vacuum. The crude for next stepwithout purification. Give the Intermediate 3 (1.50 g, crude) as ayellow solid

General Procedure for Preparation of Compound 9

To a solution of Intermediate 3 (0.50 g, 1.08 mmol, 1 eq),(E)-4-(dimethylamino)but-2-enoic acid (178.2 mg, 1.08 mmol, 1 eq, HCl),Pyridine (595.9 mg, 7.53 mmol, 608.1 uL, 7 eq) in DMF (10.0 mL) wasadded HATU (613.8 mg, 1.61 mmol, 1.5 eq). The mixture was stirred at 20°C. for 10 h. LCMS showed the reaction was completed. The mixture waspoured into H₂O (50.0 mL), then filtered and filter cake wasconcentrated in vacuum. The crude product was purified by reversed-phaseHPLC (column: Phenomenex Luna C18 200*40 mm*10 um; mobile phase: [water(0.05% HCl)-ACN]; B %: 5%-30%, 10 min) and (column: Xtimate C18 150*25mm*5 um; mobile phase: [water (10 mM NH4HCO3)-ACN]; B %: 30%-50%, 10min). Give the Compound 9 (16.0 mg, 27.2 umol, 2.53% yield, 97.9%purity) as a off-white solid.

¹H NMR: DMSO 400 MHz

12.20 (s, 1H), 10.13 (s, 1H), 8.18 (s, 1H), 7.86 (d, J=8.82 Hz, 2H),7.62 (d, J=8.60 Hz, 2H), 7.20 (t, J=9.26 Hz, 4H), 7.11 (s, 1H),6.68-6.77 (m, 1H), 6.25 (d, J=15.44 Hz, 1H), 4.43 (s, 2H), 3.87 (br d,J=4.63 Hz, 4H), 3.75 (br d, J=4.41 Hz, 4H), 3.04 (br d, J=5.07 Hz, 2H),2.16 (s, 6H)

Example 9 Synthesis of Compound 10

General Procedure for Preparation of Intermediate 2

To a stirred solution of Intermediate 1 (3.00 g, 17.9 mmol, 1 eq) inCHCl₃ (20.0 mL) was added TEA (2.74 g, 27.1 mmol, 3.77 mL, 1.51 eq) andmethanesulfonyl chloride (2.32 g, 20.2 mmol, 1.57 mL, 1.13 eq) at 0° C.The mixture was stirred at 0° C. for 2 h. TLC(Dichloromethane:Methanol=10:1, R_(f)=0.62) showed the reaction wascomplete. The mixture was poured into ice H₂O (40.0 mL) and extractedwith DCM (30.0 mL×3). Then the organic phases were washed with brine(50.0 mL) dried over Na₂SO₄, filtered and concentrated under vacuum. Thecrude for next step without purification. Give the Intermediate 2 (3.63g, crude) as a yellow solid.

¹H NMR: CDCl₃_400 MHz

8.80 (d, J=4.85 Hz, 1H), 8.15 (d, J=0.66 Hz, 1H), 7.53 (dt, J=4.91, 0.85Hz, 1H), 5.27-5.34 (m, 2H), 4.00-4.08 (m, 3H), 3.11 (s, 3H)

General Procedure for Preparation of Intermediate 4

A mixture of Intermediate 2 (2.50 g, 10.1 mmol, 1 eq), Intermediate 3(4.08 g, 20.3 mmol, 2 eq), K₂CO₃ (7.04 g, 50.9 mmol, 5 eq) in DMF (25.0mL) was degassed and purged with N₂ for 3 times, and then the mixturewas stirred at 120° C. for 5 h under N₂ atmosphere. TLC(Dichloromethane:Methanol=10:1, R_(f)=0.55) showed the reaction wascomplete. The mixture was poured into H₂O (70.0 mL) and extracted withDCM (40.0 mL×3). Then the organic phases were washed with brine (100.0mL) dried over Na₂SO₄, filtered and concentrated under vacuum. Theresidue was purified by silica gel chromatography eluted with Petroleumether:Ethyl acetate=100/1˜ 20/1˜ 10/1-1/1. Give the Intermediate 4 (1.85g, 5.29 mmol, 51.9% yield) as a yellow solid.

¹H NMR: CDCl₃_400 MHz

8.68 (d, J=5.07 Hz, 1H), 8.07 (s, 1H), 7.46-7.49 (m, 1H), 4.90 (br s,1H), 4.01 (s, 3H), 3.54 (s, 2H), 2.61 (br d, J=8.82 Hz, 1H), 2.20-2.43(m, 3H), 1.69 (br s, 2H), 1.52-1.62 (m, 1H), 1.44 (s, 9H)

General Procedure for Preparation of Intermediate 5

To a solution of Intermediate 4 (1.50 g, 4.29 mmol, 1 eq) in THF (7.00mL) was added LiOH·H₂O (540.3 mg, 12.8 mmol, 3 eq) in H₂O (7.00 mL). Themixture was stirred at 25° C. for 3 h. TLC(Dichloromethane:Methanol=10:1, R_(f)=0) showed the reaction wascomplete. The mixture was poured into H₂O (20.0 mL) and extracted withDCM (10.0 mL×3). Then the organic phases dried over Na₂SO₄, filtered andconcentrated under vacuum. The crude without purification. Give theIntermediate 5 (1.20 g, crude) as a yellow solid.

¹H NMR: DMSO_400 MHz

8.47 (br s, 1H), 7.86 (br s, 1H), 7.20-7.37 (m, 1H), 6.71 (br d, J=7.50Hz, 1H), 3.48 (br d, J=13.01 Hz, 3H), 2.65-2.78 (m, 1H), 1.74-1.87 (m,2H), 1.68 (br d, J=7.94 Hz, 2H), 1.58 (br d, J=11.91 Hz, 1H), 1.37 (brd, J=7.06 Hz, 3H), 1.35 (s, 9H).

General Procedure for Preparation of Intermediate 6

To a solution of Intermediate 5 (0.80 g, 2.39 mmol, 1 eq), Intermediate3A (704.4 mg, 2.39 mmol, 1 eq), TEA (1.69 g, 16.7 mmol, 2.32 mL, 7 eq)in DCM (10.0 mL) was added HATU (1.36 g, 3.58 mmol, 1.5 eq). The mixturewas stirred at 20° C. for 12 h. LCMS showed the reaction was complete.The mixture was poured into H₂O (40.0 mL) and extracted with DCM (20.0mL×3). Then the organic phases were washed with brine (50.0 mL) driedover Na₂SO₄, filtered and concentrated under vacuum. The crude for nextstep without purification. Give the Intermediate 6 (0.60 g, crude) as ayellow solid.

General Procedure for Preparation of Intermediate 7

To a solution of Intermediate 6 (0.50 g, 816.0 umol, 1 eq) in MeOH (5.00mL) was added HCl/MeOH (4 M, 5.00 mL, 24.51 eq). The mixture was stirredat 20° C. for 12 h. LCMS showed the reaction was complete. The mixturewas concentrated under vacuum. The crude for next step withoutpurification. Give the Intermediate 7 (0.50 g, crude, HCl) as a yellowsolid.

¹H NMR: DMSO_400 MHz

General Procedure for Preparation of Compound 10

To a solution of Intermediate 3 (0.50 g, 910.6 umol, 1 eq, HCl) in DMF(10.0 mL) was added TEA (645.0 mg, 6.37 mmol, 887.2 uL, 7 eq) andprop-2-enoyl chloride (82.4 mg, 910.6 umol, 74.2 uL, 1 eq). Then themixture was stirred at 20° C. for 12 h. LCMS showed the reaction wascomplete. The mixture was poured into H₂O (50.0 mL), then was filteredand filter cake was concentrated in vacuum. The crude product waspurified by reversed-phase HPLC (column: Phenomenex Luna C18 200*40mm*10 um; mobile phase: [water (0.05% HCl)-ACN]; B %: 10%-30%, 10 min)and (column: Xtimate C18 150*25 mm*5 um; mobile phase: [water (10 mMNH₄HCO₃)-ACN]; B %: 30%-60%, 10 min). Give the Intermediate Compound 10(20.0 mg, 35.0 umol, 3.85% yield, 99.3% purity) as a yellow solid.

¹H NMR: DMSO_400 MHz

12.20 (s, 1H), 10.73 (s, 1H), 8.68 (d, J=5.01 Hz, 1H), 8.18 (s, 1H),8.11 (s, 1H), 7.96-8.03 (m, 3H), 7.88-7.94 (m, 2H), 7.62 (d, J=4.16 Hz,1H), 7.16 (s, 1H), 6.17-6.27 (m, 1H), 6.01-6.09 (m, 1H), 5.56 (dd,J=10.15, 2.20 Hz, 1H), 3.86-3.92 (m, 4H), 3.79-3.86 (m, 1H), 3.72-3.79(m, 4H), 3.66 (s, 2H), 2.79 (br d, J=7.70 Hz, 1H), 2.65 (br d, J=11.98Hz, 1H), 1.99-2.10 (m, 1H), 1.91 (br t, J=9.90 Hz, 1H), 1.63-1.83 (m,2H), 1.46-1.62 (m, 1H), 1.12-1.32 (m, 1H).

Example 10 Synthesis of Compound 11

General Procedure for Preparation of Intermediate 2

To a solution of Intermediate 1 (0.70 g, 4.27 mmol, 1 eq), Intermediate3A (1.32 g, 4.48 mmol, 1.05 eq) and TEA (517.9 mg, 5.12 mmol, 712.4 uL,1.2 eq) in DMF (7.00 mL) was added DMAP (104.2 mg, 853.0 umol, 0.2 eq).Then the mixture was stirred at 20° C. for 16 h. LCMS showed thereaction was completed. The mixture was poured into H₂O (30.0 mL), thenfiltered and filter cake was concentrated in vacuum. The crude productwas used for next step without purification. Give the Intermediate 2(2.10 g, crude) as a yellow solid.

¹H NMR: DMSO 400 MHz

12.18 (br s, 1H), 9.50 (br s, 1H), 9.05 (br s, 1H), 8.13-8.23 (m, 3H),7.95 (s, 1H), 7.86 (br d, J=8.38 Hz, 2H), 7.71 (br d, J=8.82 Hz, 2H),7.54 (br d, J=8.38 Hz, 2H), 7.10 (s, 1H), 3.68-3.92 (m, 8H), 2.69-2.91(m, 5H)

General Procedure for Preparation of Intermediate 3

To a solution of SnCl₂·2H₂O (2.95 g, 13.0 mmol, 6 eq) in HCl (1.2 M,9.98 mL, 5.5 eq) was added Intermediate 2 (1.00 g, 2.18 mmol, 1 eq) andEtOH (5.00 mL), the mixture was stirred at 80° C. for 24 h. LCMS showedthe reaction was complete. The reaction mixture was concentrated underreduced pressure to remove EtOH. The residue was diluted with H₂O (30.0mL) and added aq. NaHCO₃ to adjust pH=8. Then the mixture was filteredand filter cake was concentrated in vacuum. The crude product was usedfor next step without purification. Give the Intermediate 3 (1.00 g,crude) as a yellow solid.

General Procedure for Preparation of Compound 11

To a solution of Intermediate 3 (0.50 g, 1.16 mmol, 1 eq in DMF 5.00 mLwas added TEA (235.6 mg, 2.33 mmol, 324.0 uL, 2 eq) and prop-2-enoylchloride (105.7 mg, 1.16 mmol, 94.9 uL, 1 eq). Then the mixture wasstirred at 20° C. for 12 h. LCMS showed the reaction was completed. Themixture was poured into H₂O (30.0 mL), then filtered and filter cake wasconcentrated in vacuum. The crude product was purified by reversed-phaseHPLC (column: Luna C18 100*30 5u; mobile phase: [water (0.04% HCl)-ACN];B %: 10%-40%, 11 min). Give Compound 11 (30.0 mg, 56.0 umol, 4.81%yield, 97.0% purity, HCl) as a yellow solid.

¹H NMR: DMSO 400 MHz

12.99 (br s, 1H), 10.11 (s, 1H), 9.16 (s, 1H), 9.00 (s, 1H), 8.31-8.41(m, 1H), 7.83-7.93 (m, 2H), 7.58 (dd, J=13.27, 8.86 Hz, 4H), 7.43 (s,1H), 7.41 (s, 1H), 7.28-7.38 (m, 1H), 6.37-6.49 (m, 1H), 6.18-6.28 (m,1H), 5.67-5.79 (m, 1H), 3.98 (br d, J=4.65 Hz, 4H), 3.79-3.86 (m, 4H)

Example 11 Synthesis of Compound 13

General Procedure for Preparation of Compound 2

To a stirred solution of compound 1 (23.0 g, 137.5 mmol, 1 eq) in CHCl₃(200.0 mL) was added TEA (21.0 g, 207.7 mmol, 28.9 mL, 1.51 eq) andmethanesulfonyl chloride (17.8 g, 155.4 mmol, 12.0 mL, 1.13 eq) at 0° C.The mixture was stirred at 0° C. for 2 h. TLC(Dichloromethane:Methanol=10:1, R_(f)=0.62) showed the reaction wascomplete. The mixture was poured into ice H₂O (400.0 mL) and extractedwith DCM (200.0 mL×3). Then the organic phases were washed with brine(500.0 mL) dried over Na₂SO₄, filtered and concentrated under vacuum.The crude for next step without purification. Give the compound 2 (33.0g, crude) as a yellow solid.

¹H NMR: (400 MHz, CDCl₃)

δ 8.78 (d, J=5.1 Hz, 1H), 8.13 (s, 1H), 7.48-7.54 (m, 1H), 5.30 (s, 2H),4.00-4.04 (m, 3H), 3.10 ppm (s, 3H)

General Procedure for Preparation of Compound 4

To a solution of compound 2 (33.0 g, 134.5 mmol, 1 eq), compound 3 (53.9g, 269.1 mmol, 2 eq), K₂CO₃ (92.9 g, 672.7 mmol, 5 eq) in DMF (300.0 mL)was degassed and purged with N₂ for 3 times, and then the mixture wasstirred at 120° C. for 5 h under N₂ atmosphere. TLC(Dichloromethane:Methanol=10:1, R_(f)=0.55) showed the reaction wascomplete. The mixture was poured into H₂O (500.0 mL) and extracted withDCM (300.0 mL×3). Then the organic phases were washed with brine (1.00L) dried over Na₂SO₄, filtered and concentrated under vacuum. Theresidue was purified by silica gel chromatography eluted with Petroleumether:Ethyl acetate=100/1˜20/1˜10/1-1/1. Give the compound 4 (43.0 g,123.0 mmol, 91.4% yield) as a yellow solid.

General Procedure for Preparation of Compound 5

To a solution of compound 4 (43.0 g, 123.0 mmol, 1 eq) in THF (200.0 mL)was added LiOH·H₂O (15.4 g, 369.1 mmol, 3 eq) in H₂O (200.0 mL). Themixture was stirred at 20° C. for 3 h. TLC(Dichloromethane:Methanol=10:1, R_(f)=0) showed the reaction wascomplete. The mixture was poured into H₂O (100.0 mL) and extracted withDCM:MeOH=10:1 (100.0 mL×7). Then the organic phases dried over Na₂SO₄,filtered and concentrated under vacuum. The crude for next step withoutpurification. Give the compound 5 (33.0 g, crude) as a yellow solid.

¹H NMR: (400 MHz, DMSO)

δ 8.37 (d, J=4.9 Hz, 1H), 7.90 (s, 1H), 7.31-7.40 (m, 1H), 6.74 (br d,J=7.7 Hz, 1H), 3.46-3.61 (m, 2H), 3.40 (br s, 1H), 2.74 (br d, J=7.9 Hz,1H), 2.59 (br d, J=9.7 Hz, 1H), 1.76-1.91 (m, 2H), 1.70 (br d, J=9.0 Hz,1H), 1.55-1.65 (m, 1H), 1.42-1.50 (m, 1H), 1.35 (s, 9H), 1.04-1.19 ppm(m, 1H)

General Procedure for Preparation of Compound 6

To a solution of compound 5 (5.50 g, 18.6 mmol, 1 eq), compound 3A (9.99g, 29.8 mmol, 1.6 eq), DIEA (6.02 g, 46.5 mmol, 8.11 mL, 2.5 eq) in DCM(100.0 mL) was added T₃P (17.7 g, 27.9 mmol, 16.6 mL, 50% purity, 1.5eq). The mixture was stirred at 20° C. for 12 h. TLC(Dichloromethane:Methanol=10:1, R_(f)=0.51) showed the reaction wascomplete. The mixture was poured into H₂O (150.0 mL) and extracted withDCM (100.0 mL×3). Then the organic phases were washed with brine (500.0mL×3) dried over Na₂SO₄, filtered and concentrated under vacuum. Thecrude product was triturated with MeCN (150.0 mL) at 20° C. for 2 h.Give the compound 5 (4.00 g, crude) as a yellow solid.

General Procedure for Preparation of Compound 7

To a solution of compound 5 (8.00 g, 13.0 mmol, 1 eq) in MeOH (50.0 mL)was added HCl/MeOH (4 M, 133.3 mL, 40.8 eq). The mixture was stirred at20° C. for 12 h. TLC (Dichloromethane:Methanol=10:1, R_(f)=0) showed thereaction was complete. The mixture was concentrated under vacuum. Thecrude product was purified by reversed-phase HPLC (column: Phenomenexluna C18 250*50 mm*15 um; mobile phase: [water (0.05% HCl)-ACN]; B %:1%-25%, 20 min). Give the 7 (7.00 g, crude, HCl) as a yellow solid.

¹H NMR: (400 MHz, DMSO)

δ 13.07 (br s, 1H), 12.05 (br s, 1H), 10.88 (s, 1H), 8.86 (br d, J=4.4Hz, 1H), 8.41 (br s, 3H), 8.35 (s, 1H), 8.02-8.10 (m, 3H), 7.95-8.01 (m,2H), 7.42 (br s, 1H), 4.59 (br s, 2H), 4.00 (br d, J=4.4 Hz, 6H), 3.83(br d, J=4.2 Hz, 4H), 3.33-3.69 (m, 2H), 2.83-3.13 (m, 2H), 1.84-2.15(m, 3H), 1.53 (br s, 1H), 1.15-1.29 ppm (m, 1H)

General Procedure for Preparation of Compound 13

To a solution of 7 (4.00 g, 7.29 mmol, 1 eq, HCl),(E)-4-(dimethylamino)but-2-enoic acid (1.21 g, 7.29 mmol, 1 eq, HCl),DIEA (2.82 g, 21.8 mmol, 3.81 mL, 3 eq) in DCM (50.0 mL) was added T₃P(4.64 g, 14.5 mmol, 4.33 mL, 2 eq). The mixture was stirred at 20° C.for 12 h. LCMS: (ET22820-211-P1A1) showed the reaction was complete. Thereaction mixture was poured into H₂O (100.0 mL) and extracted with DCM(50.0 mL×3). Then the organic phases were washed with brine (100.0 mL)dried over Na₂SO₄, filtered and concentrated under vacuum. The crudeproduct was purified by reversed-phase HPLC (column: Phenomenex luna c18250 mm*100 mm*10 um; mobile phase: [water (0.05% HCl)-ACN]; B %: 1%-25%,25 min). Give the Compound 13 (0.70 g, 1.09 mmol, 15.0% yield, 97.4%purity) as a yellow solid.

¹H NMR: (400 MHz, DMSO)

δ 13.35 (br s, 1H), 11.49 (br s, 1H), 11.01-11.18 (m, 1H), 10.89 (s,1H), 8.87 (d, J=4.9 Hz, 1H), 8.69 (br d, J=7.5 Hz, 1H), 8.32-8.48 (m,2H), 7.94-8.13 (m, 5H), 7.50 (s, 1H), 6.57-6.77 (m, 1H), 6.17-6.33 (m,1H), 4.56 (br s, 2H), 4.02-4.08 (m, 5H), 3.85 (br d, J=4.8 Hz, 6H),3.30-3.42 (m, 2H), 2.87-3.00 (m, 1H), 2.75-2.82 (m, 1H), 2.66-2.74 (m,6H), 1.75-2.08 (m, 3H), 1.61-1.75 (m, 1H), 1.36-1.52 ppm (m, 1H)

General Procedure for Preparation of Compound 3

To a solution of compound 1 (50.0 g, 325.5 mmol, 1 eq), sodium;2-methylpropan-2-olate (32.8 g, 341.8 mmol, 1.05 eq) in THF (350.0 mL)was added dropwise compound 2 (62.6 g, 354.8 mmol, 45.4 mL, 1.09 eq) at10° C. The mixture was stirred at 25° C. for 2 h. TLC (Petroleumether/Ethyl acetate=1/1, R_(f)=0.59) showed the reaction was completed.The reaction mixture was added H₂O (100.0 mL), filtered and the filtercake was washed with MeOH (50.0 mL×3), concentrated in vacuum. Theresidue was used for the next step without purification. Give compound 3(80.0 g, 272.3 mmol, 83.6% yield) as a white solid.

¹H NMR: DMSO 400 MHz

8.79-8.85 (m, 1H), 8.11-8.20 (m, 3H), 7.74-7.81 (m, 1H), 7.64-7.72 (m,2H), 6.97 (d, J=4.0 Hz, 1H)

General Procedure for Preparation of Compound 4

To a solution of compound 3 (50.0 g, 170.2 mmol, 1 eq) in THE (300.0 mL)was added drop wise LDA (2 M, 127.6 mL, 1.5 eq) at −78° C. Then themixture was stirred at −78° C. for 1 h. Then I₂ (56.1 g, 221.2 mmol,44.5 mL, 1.3 eq) in THE (100.0 mL) was added to the mixture. The mixturewas stirred at −78° C. for 1 h. TLC (Petroleum ether/Ethyl acetate=1/1,R_(f)=0.71) showed the reaction was completed. HCl (1M, 200.0 mL) wasadded to the mixture. Then the mixture was concentrated in vacuum toremove THF. The residue was diluted with H₂O (100.0 mL), extracted withEtOAc (300.0 mL×3). The combined organic layers were washed with brine(500.0 mL), dried over Na₂SO₄, concentrated in vacuum. The crude productwas triturated with MeCN (200.0 mL) at 25° C. for 2 h. Give compound 4(50.0 g, 119.1 mmol, 70.0% yield) as a off-white solid.

¹H NMR: DMSO 400 MHz

8.75-8.79 (m, 1H), 8.08-8.14 (m, 2H), 7.75-7.82 (m, 1H), 7.65-7.73 (m,2H), 7.38 (s, 1H)

General Procedure for Preparation of Compound 1A

To a solution of compound 4 (70.0 g, 166.8 mmol, 1 eq) in THF (400.0 mL)was added NaOH/MeOH (5 M, 237.8 mL, 7.13 eq). Then the mixture wasstirred at 25° C. for 1 h. TLC (Petroleum ether/Ethyl acetate=0/1,R_(f)=0.62) showed the reaction was completed. The reaction mixture wasconcentrated under reduced pressure to remove THE and MeOH. The residuewas diluted with NH₄Cl (aq, 500.0 mL), filtered and the filter cake wasconcentrated under reduced pressure to give a residue. The crude productwas triturated with MeCN (50.0 mL) at 25° C. for 2 h. Give compound 1A(40.0 g, 143.1 mmol, 85.8% yield) as a brown solid.

¹H NMR: DMSO 400 MHz

13.14 (br s, 1H), 8.47-8.59 (m, 1H), 6.89 (s, 1H)

General Procedure for Preparation of Compound 2A

A mixture of compound 1A (40.0 g, 143.1 mmol, 1 eq), morpholine (24.9 g,286.2 mmol, 25.1 mL, 2 eq) in n-butanol (200.0 mL) was degassed andpurged with N₂ for 3 times, and then the mixture was stirred at 100° C.for 12 h under N₂ atmosphere. TLC (Dichloromethane/Methanol=10/1,R_(f)=0.62) showed the reaction was completed. The reaction mixture wasfiltered and the filter cake was concentrated. The crude product wasused for the next step without purification. Give compound 2A (40.0 g,121.1 mmol, 84.6% yield) as a brown solid

¹H NMR: DMSO 400 MHz

12.27 (br s, 1H), 8.08 (s, 1H), 6.88 (s, 1H), 3.77-3.82 (m, 4H),3.67-3.72 (m, 4H)

General Procedure for Preparation of Compound 3A

A solution of compound 2A (20.0 g, 60.5 mmol, 1 eq),(4-aminophenyl)boronic acid (15.7 g, 90.8 mmol, 1.5 eq, HCl), K₂CO₃(50.2 g, 363.5 mmol, 6 eq) in dioxane (100.0 mL) and H₂O (25.0 mL) wasstirred at 25° C. for 0.5 h. Then Pd(dppf)Cl₂ (4.43 g, 6.06 mmol, 0.1eq) was added. The mixture was stirred at 100° C. for 12 h. TLC(Dichloromethane/Methanol=10/1, R_(f)=0.47) showed the reaction wascompleted. The reaction mixture was concentrated under reduced pressureto remove dioxane. The residue was diluted with H₂O (150.0 mL) andextracted with EtOAc (300.0 mL×5). The combined organic layers werewashed with brine (300.0 mL), dried over Na₂SO₄, filtered andconcentrated under reduced pressure to give a residue. The crude productwas triturated with MeOH (60.0 mL) for 2 h at 25° C. Give compound 3A(8.50 g, 28.7 mmol, 47.5% yield) as a brown solid

¹H NMR: DMSO 400 MHz

11.92 (br s, 1H), 8.12 (s, 1H), 7.57 (br d, J=8.4 Hz, 3H), 6.83 (s, 1H),6.59 (br d, J=8.4 Hz, 2H), 5.32 (s, 2H), 3.83 (br d, J=4.6 Hz, 4H), 3.74(br d, J=4.6 Hz, 4H).

Example 12 Synthesis of Compound 15

To a solution of Intermediate 6 (6.00 g, 11.49 mmol, 1 eq, HCl),(E)-4-(dimethylamino)but-2-enoic acid (1.90 g, 11.49 mmol, 1 eq, HCl),DIEA (3.71 g, 28.74 mmol, 5.01 mL, 2.5 eq) in DCM (40.0 mL) was addedT₃P (10.9 g, 17.24 mmol, 10.2 mL, 50% purity, 1.5 eq). The mixture wasstirred at 20° C. for 1 hr. LC-MS showed˜0% of Intermediate 6 wasremained. Several new peaks were shown on LC-MS and ˜39% of desiredcompound was detected. The reaction mixture was concentrated underreduced pressure to give a residue. The crude product was purified byreversed-phase HPLC (0.1% FA condition). Compound 15 (0.800 g, 1.26mmol, 10.9% yield, HCl, 96.8 purity) was obtained as a orange solid.

¹H NMR: (400 MHz, DMSO)

δ 13.25-13.10 (m, 1H), 13.09-12.95 (m, 1H), 11.40-11.19 (m, 1H),11.05-10.86 (m, 1H), 10.44 (s, 1H), 9.32 (br d, J=6.6 Hz, 1H), 8.38-8.32(m, 1H), 7.99-7.85 (m, 3H), 7.64-7.54 (m, 2H), 7.45-7.38 (m, 1H),6.80-6.64 (m, 1H), 6.46-6.42 (m, 1H), 6.35-6.22 (m, 1H), 6.11-6.00 (m,1H), 4.78-4.68 (m, 1H), 4.53-4.42 (m, 2H), 4.10 (br s, 2H), 4.06-3.98(m, 5H), 3.89-3.82 (m, 5H), 2.78-2.69 (m, 6H)

Example 13 Synthesis of Compound 19

General Procedure for Preparation of Compound 1

To a solution of compound 3A (1.00 g, 3.39 mmol, 1 eq), compound 1b(1.04 g, 3.39 mmol, 1 eq), TEA (2.40 g, 23.7 mmol, 3.30 mL, 7 eq) in DMF(12.0 mL) was added HATU (1.93 g, 5.08 mmol, 1.5 eq). The mixture wasstirred at 20° C. for 12 hrs. LCMS showed the reaction was complete. Themixture was poured into H₂O (150.0 mL), then was filtered and filtercake was concentrated in vacuum. The crude product was purified byreversed-phase HPLC (column: Phenomenex luna C18 250*50 mm*10 um; mobilephase: [water (0.05% HCl)-ACN]; B %: 10%-30%, 20 min). Give the compound1 (0.500 g, 804.9 umol, 23.7% yield, HCl) as a yellow solid.

General Procedure for Preparation of Compound 2

To a solution of compound 1 (0.500 g, 804.9 umol, 1 eq, HCl) in MeOH(5.00 mL) was added HCl/MeOH (4 M, 18.8 mL, 93.5 eq). The mixture wasstirred at 20° C. for 12 hrs. LCMS showed the reaction was complete. Themixture was concentrated in vacuum. The crude for next step withoutpurification. Give the compound 2 (0.450 g, crude, HCl) as a yellowsolid.

General Procedure for Preparation of Compound 19

To a solution of compound 2 (0.300 g, 575.8 umol, 1 eq, HCl), TEA (582.6mg, 5.76 mmol, 801.4 uL, 10 eq) in DCM (10.0 mL) was added prop-2-enoylchloride (52.1 mg, 575.8 umol, 46.9 uL, 1 eq) in DCM (2.00 mL) dropwiseat −20° C. The mixture was stirred at −20° C. for 0.5 hr. LCMS showedthe reaction was complete. The mixture was concentrate in vacuum. Thecrude product was purified by reversed-phase HPLC (column: PhenomenexLuna C18 150*30 mm*5 um; mobile phase: [water (0.04% HCl)-ACN]; B %:5%-35%, 10 min) and (column: Phenomenex Luna C18 150*30 mm*5 um; mobilephase: [water (0.04% HCl)-ACN]; B %: 5%-35%, 10 min) (column: PhenomenexLuna C18 150*30 mm*5 um; mobile phase: [water (0.04% HCl)-ACN]; B %:5%-35%, 10 min). Give the Compound 19 (15.0 mg, 24.8 umol, 4.32% yield,95.4% purity, HCl) as a yellow solid.

¹H NMR: DMSO Varian_S_400 MHz

13.01 (br s, 2H), 11.10 (s, 1H), 10.31 (s, 1H), 8.99 (d, J=6.72 Hz, 1H),8.33 (s, 1H), 7.95 (d, J=8.68 Hz, 2H), 7.87 (d, J=7.21 Hz, 1H), 7.58 (d,J=8.80 Hz, 2H), 7.38 (br s, 1H), 6.44 (dd, J=7.21, 2.32 Hz, 1H),6.20-6.28 (m, 1H), 6.11-6.18 (m, 1H), 6.08 (d, J=2.20 Hz, 1H), 5.64-5.71(m, 1H), 4.66-4.78 (m, 1H), 4.47 (br s, 2H), 4.07 (br s, 2H), 3.99 (brd, J=4.65 Hz, 5H), 3.78-3.86 (m, 4H)

General Procedure for Preparation of Compound 3

To a solution of compound 1 (50.0 g, 325.5 mmol, 1 eq) in THF (350.0 mL)was added t-BuONa (32.8 g, 341.8 mmol, 1.05 eq), then compound 2 (57.5g, 325.5 mmol, 41.6 mL, 1 eq) was added to the mixture at 10° C. Thereaction was stirred at 25° C. for 5 hrs. TLC (Petroleum ether/Ethylacetate=1/1, R_(f)=0.59) showed the reaction was completed. The reactionmixture was added H₂O (100.0 mL), filtered and the filter cake waswashed with MeOH (50.0 mL×3), concentrated in vacuum. The residue wasused for the next step without purification. Give compound 3 (90.0 g,306.4 mmol, 94.1% yield) as a white solid.

¹H NMR: DMSO Bruker_E_400 MHz

8.80-8.85 (m, 1H), 8.13-8.19 (m, 3H), 7.76-7.83 (m, 1H), 7.64-7.71 (m,2H), 6.96-6.99 (m, 1H)

General Procedure for Preparation of Compound 4

Two reactions were carried out in parallel.

To a solution of compound 3 (40.0 g, 136.1 mmol, 1 eq) in THE (150.0 mL)was dropwise added LDA (2 M, 102.1 mL, 1.5 eq) at −78° C. The reactionwas stirred at −78° C. for 1 hr. After that 12 (44.9 g, 177.0 mmol, 35.6mL, 1.3 eq) in THE (50.0 mL) was added dropwise to the reaction mixture.The reaction was stirred at −78° C. for 1 hr. TLC (Petroleum ether/Ethylacetate=1/1, R_(f)=0.61) showed the reaction was completed. Tworeactions were combined for workup. The mixture was added HCl (1M, 200.0mL), concentrated, filtered. The filter cake was triturated with MeCN(100.0 mL) for 2 hrs, filtered and concentrated in vacuum. Give compound4 (80.0 g, 190.6 mmol, 70.0% yield) as a off-white solid

¹H NMR: DMSO Varian_S_400 MHz

8.75-8.77 (m, 1H), 8.07-8.13 (m, 2H), 7.76-7.81 (m, 1H), 7.65-7.72 (m,2H), 7.34-7.38 (m, 1H

General Procedure for Preparation of Compound 1A

To a solution of compound 4 (60.0 g, 142.9 mmol, 1 eq) in THE (400.0 mL)was added NaOH/MeOH (5 M, 200.1 mL, 7 eq). The reaction was stirred at25° C. for 1 hr. TLC (Petroleum ether/Ethyl acetate=0/1, R_(f)=0.57)showed the reaction was completed. The reaction mixture was concentratedunder reduced pressure to remove THE and MeOH. The residue was dilutedwith NH₄Cl (aq. 500.0 mL), filtered and the filter cake was concentratedunder reduced pressure to give a residue. The crude product wastriturated with MeCN (50.0 mL) at 25° C. for 2 hrs. Give compound 1A(35.0 g, crude) as a off-white solid

¹H NMR: DMSO Varian_Y_400 MHz

13.11-13.18 (m, 1H), 8.47-8.55 (m, 1H), 6.81-6.92 (m, 1H)

General Procedure for Preparation of Compound 2A

A solution of compound 1A (35.0 g, 125.2 mmol, 1 eq), morpholine (21.8g, 250.4 mmol, 22.0 mL, 2 eq) in n-butanol (200.0 mL) was stirred at100° C. for 12 hrs. TLC (Dichloromethane/Methanol=10/1, R_(f)=0.51)showed the reaction was completed. The reaction mixture was filtered andthe filter cake was concentrated. The crude product was used for thenext step without purification. Give compound 2A (40.0 g, crude) as aoff-white solid.

General Procedure for Preparation of Compound 3A

A solution of compound 2A (40.0 g, 121.1 mmol, 1 eq),(4-aminophenyl)boronic acid (31.5 g, 181.7 mmol, 1.5 eq, HCl), K₂CO₃(100.4 g, 727.0 mmol, 6 eq) in dioxane (140.0 mL) and H₂O (70.0 mL) wasstirred at 25° C. for 0.5 hr. Then Pd(dppf)Cl₂ (8.87 g, 12.1 mmol, 0.1eq) was added. The reaction was stirred at 100° C. for 12 hrs. TLC(Dichloromethan/Methanol=10/1, R_(f)=0.42) showed the reaction wascompleted. The reaction mixture was diluted with H₂O (200.0 mL) andextracted with EtOAc (500.0 mL×5). The combined organic layers werewashed with brine (300.0 mL), dried over Na₂SO₄, filtered andconcentrated under reduced pressure to give a residue. The crude productwas triturated with MeOH (50.0 mL) at 25° C. for 10 hrs. Give compound3A (13.0 g, 44.0 mmol, 36.3% yield) as a off-white solid

¹H NMR: DMSO Varian_S_400 MHz

11.91 (br s, 1H), 8.10-8.15 (m, 1H), 7.53-7.62 (m, 2H), 6.83 (s, 1H),6.56-6.64 (m, 2H), 5.23-5.38 (m, 2H), 3.83 (br d, J=4.4 Hz, 4H),3.70-3.77 (m, 4H)

General Procedure for Preparation of Compound 2a

To a solution of compound 1a (10.0 g, 58.1 mmol, 1 eq) in THF (70.0 mL)was added dropwise LDA (2 M, 69.7 mL, 2.4 eq) at −78° C. Then themixture was stirred at −78° C. for 15 min. After that dimethyl carbonate(6.28 g, 69.7 mmol, 5.87 mL, 1.2 eq) was added dropwise to the mixture.The reaction was stirred at 0° C. for 4 hrs. TLC (Petroleum ether:Ethylacetate=3:1, R_(f)=0.57) showed the reaction was completed. The reactionmixture was quenched by addition HCl (1M, 100.0 mL), and then dilutedwith H₂O (50.0 mL) and extracted with EtOAc (100.0 mL×3). The combinedorganic layers were washed with brine (30.0 mL), dried over Na₂SO₄,filtered and concentrated under reduced pressure to give a residue. Theresidue was purified by column chromatography (SiO₂, Petroleumether/Ethyl acetate=30/1 to 0/1). Give compound 2a (9.00 g, 39.1 mmol,67.3% yield) as a brown oil.

General Procedure for Preparation of Compound 3a

To a solution of compound 2a (3.00 g, 13.0 mmol, 1 eq) in DMF (30.0 mL)was added tert-butyl N-(azetidin-3-yl)carbamate (2.78 g, 13.3 mmol, 1.02eq, HCl) dicesium; carbonate (8.50 g, 26.0 mmol, 2 eq) and[2-(2-aminoethyl)phenyl]-chloro-palladium;dicyclohexyl-[2-(2,6-dimethoxyphenyl)phenyl]phosphane;2-methoxy-2-methyl-propane (496.0 mg, 652.0 umol, 0.05 eq), the mixturewas stirred at 80° C. for 12 hrs. TLC (Dichloromethane:Methanol=10:1,R_(f)=0.28) showed the reaction was complete. The mixture was pouredinto H₂O (100.0 mL) and extracted with EtOAc (50.0 mL×3). Then theorganic phases were washed with brine (200.0 mL) dried over Na₂SO₄,filtered and concentrated under vacuum. The residue was purified bysilica gel chromatography eluted with Petroleum ether:Ethylacetate=100/1˜ 20/1˜ 10/1-1/1. Give the compound 3a (2.00 g, crude) as ayellow oil.

General Procedure for Preparation of Compound 1b

To a solution of compound 3a (2.00 g, 6.22 mmol, 1 eq) in MeOH (10.0 mL)was added NaOH (497.8 mg, 12.4 mmol, 2 eq) and H₂O (10.0 mL). Themixture was stirred at 20° C. for 3 hrs. TLC(Dichloromethane:Methanol=10:1, R_(f)=0) showed the reaction wascomplete. The reaction mixture was concentrated under reduced pressureto remove MeOH. The residue was diluted with H₂O (30.0 mL) and added 0.5M HCl to adjust pH=6. Then the mixture was extracted with DCM (20.0mL×3). The aqueous layer was concentrated under reduced pressure. Theresidue was diluted with MeOH (20.0 mL), filtered and concentrated underreduced pressure to give a residue. The crude for next step withoutpurification. Give the compound 1b (1.50 g, crude) as a yellow solid.

Example 14 Synthesis of Compound 23

General Procedure for Preparation of Compound 2

A solution of compound 1 (40.0 g, 230.4 mmol, 1 eq) and morpholine (42.1g, 483.9 mmol, 42.5 mL, 2.1 eq) in EtOH (400.0 mL) was stirred at 80° C.for 2 hrs. TLC (Petroleum ether:Ethyl acetate=3:1, R_(f)=0.44) showedthe reaction was complete. The reaction mixture was concentrated to givea residue. The residue was extracted with EtOAc (200.0 mL), filtered.The filter was concentrated in vacuum to give a residue. The residue wasused for the next step without purification. Give the compound 2 (51.0g, crude) as a yellow solid.

¹H NMR: CDCl₃ Bruker_F_400 MHz

7.77 (d, J=5.62 Hz, 1H), 6.07 (d, J=5.62 Hz, 1H), 5.98 (br s, 2H),3.74-3.80 (m, 4H) 3.39-3.45 (m, 4H)

General Procedure for Preparation of Compound 3

To a solution of SnCl₂·2H₂O (161.0 g, 713.6 mmol, 4 eq) in HCl (1.2 M,297.3 mL, 2 eq) was added compound 2 (40.0 g, 178.4 mmol, 1 eq) and EtOH(50.0 mL), the mixture was stirred at 80° C. for 12 hrs. TLC(Dichloromethane:Methanol=10:1, R_(f)=0.16) showed the reaction wascomplete. The reaction mixture was concentrated under reduced pressureto remove EtOH. The residue was diluted with H₂O (100.0 mL) and addeda.q. NaHCO₃ to adjust pH=10. Then the mixture was extracted with EtOAc(50.0 mL×7). The combined organic layers were washed with brine (200.0mL), dried over Na₂SO₄, filtered and concentrated under reduced pressureto give a residue. The crude for next step without purification. Givethe compound 3 (28.0 g, crude) as a red solid.

General Procedure for Preparation of Compound 4

To a solution of compound 3 (23.0 g, 118.4 mmol, 1 eq) in Tol. (200.0mL) was added MgSO₄ (14.2 g, 118.4 mmol, 1 eq) and 4-nitrobenzaldehyde(19.6 g, 130.2 mmol, 1.1 eq). The mixture was stirred at 115° C. for 12hrs. TLC (Dichloromethane:Methanol=10:1, R_(f)=0.65) showed the reactionwas complete. The solution was filtered and concentrated under reducedpressure to give a residue. The crude for next step withoutpurification. Give the compound 4 (35.0 g, crude) as red oil. (35.0 gand 15.0 g total give compound 4 50.0 g).

General Procedure for Preparation of Compound 5

To a solution of SnCl₂·2H₂O (110.9 g, 491.8 mmol, 4 eq) in HCl (1.2 M,204.9 mL, 2 eq) was added compound 4 (40.0 g, 122.9 mmol, 1 eq) and EtOH(100.0 mL), the mixture was stirred at 80° C. for 12 hrs. TLC(Dichloromethane:Methanol=10:1, R_(f)=0.38) showed the reaction wascomplete. The reaction mixture was concentrated under reduced pressureto remove EtOH. The residue was diluted with H₂O (500.0 mL) and addeda.q. NaHCO₃ to adjust pH=7. Then the mixture was extracted with EtOAc(200.0 mL×3). The combined organic layers were washed with brine (500.0mL), dried over Na₂SO₄, filtered and concentrated under reduced pressureto give a residue. The residue was purified by silica gel chromatographyeluted with (Petroleum ether:Ethyl acetate=100/1˜ 20/1˜ 10/1-1/1). Givethe compound 5 (20.0 g, crude) as a yellow solid.

General Procedure for Preparation of Compound 6

To solution of compound 5 (2.00 g, 6.77 mmol, 1 eq) in THE (80.0 mL) wasadded K₂CO₃ (2.81 g, 20.3 mmol, 3 eq) at 25° C. After 30 min, phenylcarbonochloridate (1.27 g, 8.13 mmol, 1.02 mL, 1.2 eq) was added to thereaction. Then the reaction was stirred at 25° C. for 2 hrs. Then thecompound 1d (1.31 g, 4.94 mmol, 0.73 eq), TEA (3.43 g, 33.8 mmol, 4.71mL, 5 eq) and DMAP (413.6 mg, 3.39 mmol, 0.5 eq) was added to thereaction. The reaction was stirred at 80° C. for 12 hrs. LCMS showed thereaction was complete. The mixture was filtered and filter liquor wasconcentrated in vacuum. The crude product was purified by reversed-phaseHPLC (column: Phenomenex luna c18 250 mm*100 mm*10 um; mobile phase:[water (10 mM NH₄HCO₃)-ACN]; B %: 35%-65%, 25 min). Give the compound 6(1.00 g, 1.54 mmol, 22.6% yield, 90.0% purity) as a yellow solid.

General Procedure for Preparation of Compound 7

To a solution of compound 6 (0.600 g, 1.02 mmol, 1 eq) in MeOH (5.00 mL)was added HCl/MeOH (4 M, 12.8 mL, 50 eq). The mixture was stirred at 20°C. for 5 hrs. LCMS showed the reaction was complete. The mixture wasconcentrated in vacuum. The crude for next step without purification.Give the compound 7 (0.600 g, crude, HCl) as a yellow solid.

General Procedure for Preparation of Compound 23

To a solution of compound 6 (0.400 g, 766.2 umol, 1 eq, HCl), TEA (775.4mg, 7.66 mmol, 1.07 mL, 10 eq) in DCM (10.0 mL) was added prop-2-enoylchloride (69.3 mg, 766.2 umol, 62.4 uL, 1 eq) in DCM (2.00 mL) dropwiseat −20° C. The mixture was stirred at −20° C. for 0.5 hr. LCMS showedthe reaction was complete. The mixture was poured into H₂O (100.0 mL),then was filtered and filter cake was concentrated in vacuum. The crudeproduct was purified by reversed-phase HPLC (column: Luna C18 150*25 5u;mobile phase: [water (0.04% HCl)-ACN]; B %: 10%-25%, 10 min) and(column: Luna C18 150*25 5u; mobile phase: [water (0.04% HCl)-ACN]; B %:10%-25%, 10 min). Give the Compound 23 (35.0 mg, 59.8 umol, 7.81% yield,98.4% purity, HCl) as a Off-white solid.

¹H NMR: DMSO Varian_S_400 MHz

14.32 (br s, 1H), 13.07 (br s, 2H), 10.99 (br s, 1H), 10.44 (br s, 1H),8.97 (br d, J=6.84 Hz, 1H), 8.18 (br d, J=8.38 Hz, 2H), 7.88 (br d,J=7.06 Hz, 1H), 7.61-7.77 (m, 3H), 7.21 (br d, J=6.84 Hz, 1H), 6.44 (brd, J=6.61 Hz, 1H), 6.07-6.30 (m, 3H), 5.68 (dd, J=10.03, 2.09 Hz, 1H),4.73 (br d, J=6.17 Hz, 1H), 4.46 (br s, 2H), 4.31 (br s, 4H), 4.06 (brs, 2H), 3.87 (br s, 4H)

General Procedure for Preparation of Compound 1c

A solution of compound 1a (10.0 g, 63.0 mmol, 1 eq) compound 1b (19.7 g,94.6 mmol, 1.5 eq, HCl) NaHCO₃ (13.2 g, 157.6 mmol, 6.13 mL, 2.5 eq) inDMSO (70.0 mL) was stirred at 80° C. for 12 hrs. TLC (Petroleumether/Ethyl acetate=0/1, R_(f)=0.24) showed the reaction was completed.The reaction mixture was poured into water (500.0 mL), extracted withEtOAc (300.0 mL×3). The combined organic layers were washed with brine(300.0 mL), dried over Na₂SO₄, concentrated in vacuum. The residue waspurified by column chromatography (SiO₂, Petroleum ether/Ethylacetate=50/1 to 1/1). Give compound 1c (13.0 g, 44.1 mmol, 70.0% yield)as a yellow solid.

General Procedure for Preparation of Compound 1d

To a solution of compound 1c (11.0 g, 37.3 mmol, 1 eq) in MeOH (110.0mL) was added Pd/C (5.00 g, 37.3 mmol, 10.0% purity, 1 eq) under N₂. Thesuspension was degassed under vacuum and purged with H₂ several times.The mixture was stirred under H₂ (50.0 psi) at 25° C. for 3 hrs. TLC(Petroleum ether/Ethyl acetate=0/1, R_(f)=0.07) showed the startingmaterial was consumed completely. The reaction mixture was filtered andthe filter was concentrated. The crude product was used for the nextstep without purification. Give the compound 1d (9.00 g, 34.0 mmol,91.1% yield) as a light yellow solid.

Example 15 Synthesis of Compound 24

General Procedure for Preparation of Compound 2

A solution of compound 1 (40.0 g, 230.4 mmol, 1 eq) and morpholine (42.1g, 483.9 mmol, 42.5 mL, 2.1 eq) in EtOH (400.0 mL) was stirred at 80° C.for 2 hrs. TLC (Petroleum ether: Ethyl acetate=3:1, R_(f)=0.44) showedthe reaction was complete. The reaction mixture was concentrated to givea residue. The residue was extracted with EtOAc (200.0 mL), filtered.The filter was concentrated in vacuum to give a residue. The residue wasused for the next step without purification. Give the compound 2 (51.0g, crude) as a yellow solid.

¹H NMR: CDCl₃ Bruker_F_400 MHz

7.77 (d, J=5.62 Hz, 1H), 6.07 (d, J=5.62 Hz, 1H), 5.98 (br s, 2H),3.74-3.80 (m, 4H) 3.39-3.45 (m, 4H)

General Procedure for Preparation of Compound 3

To a solution of SnCl₂·2H₂O (161.0 g, 713.6 mmol, 4 eq) in HCl (1.2 M,297.3 mL, 2 eq) was added compound 2 (40.0 g, 178.4 mmol, 1 eq) and EtOH(50.0 mL), the mixture was stirred at 80° C. for 12 hrs. TLC(Dichloromethane:Methanol=10:1, R_(f)=0.16) showed the reaction wascomplete. The reaction mixture was concentrated under reduced pressureto remove EtOH. The residue was diluted with H₂O (100.0 mL) and addeda.q. NaHCO₃ to adjust pH=10. Then the mixture was extracted with EtOAc(50.0 mL×7). The combined organic layers were washed with brine (200.0mL), dried over Na₂SO₄, filtered and concentrated under reduced pressureto give a residue. The crude for next step without purification. Givethe compound 3 (28.0 g, crude) as a red solid.

General Procedure for Preparation of Compound 4

To a solution of compound 3 (23.0 g, 118.4 mmol, 1 eq) in Tol. (200.0mL) was added MgSO₄ (14.2 g, 118.4 mmol, 1 eq) and 4-nitrobenzaldehyde(19.6 g, 130.2 mmol, 1.1 eq). The mixture was stirred at 115° C. for 12hrs. TLC (Dichloromethane:Methanol=10:1, R_(f)=0.65) showed the reactionwas complete. The solution was filtered and concentrated under reducedpressure to give a residue. The crude for next step withoutpurification. Give the compound 4 (35.0 g, crude) as a red oil.

General Procedure for Preparation of Compound 5

To a solution of SnCl₂·2H₂O (110.9 g, 491.8 mmol, 4 eq) in HCl (1.2 M,204.9 mL, 2 eq) was added compound 4 (40.0 g, 122.9 mmol, 1 eq) and EtOH(100.0 mL), the mixture was stirred at 80° C. for 12 hrs. TLC(Dichloromethane:Methanol=10:1, R_(f)=0.38) showed the reaction wascomplete. The reaction mixture was concentrated under reduced pressureto remove EtOH. The residue was diluted with H₂O (500.0 mL) and addeda.q. NaHCO₃ to adjust pH=7. Then the mixture was extracted with EtOAc(200.0 mL×3). The combined organic layers were washed with brine (500.0mL), dried over Na₂SO₄, filtered and concentrated under reduced pressureto give a residue. The residue was purified by silica gel chromatographyeluted with Petroleum ether:Ethyl acetate=100/1˜ 20/1˜ 10/1-1/1. Givethe compound 5 (20.0 g, crude) as a yellow solid.

General Procedure for Preparation of Compound 6

To a solution of compound 5 (1.70 g, 5.76 mmol, 1 eq), compound 1b (1.77g, 5.76 mmol, 1 eq), TEA (4.08 g, 40.2 mmol, 5.61 mL, 7 eq) in DMF (10.0mL) was added HATU (3.28 g, 8.63 mmol, 1.5 eq). The mixture was stirredat 20° C. for 12 hrs. LCMS showed the reaction was complete. The mixturewas poured into H₂O (150.0 mL), then was filtered and filter cake wasconcentrated in vacuum. The crude product was purified by reversed-phaseHPLC (column: Phenomenex luna C18 250*50 mm*10 um; mobile phase: [water(0.1% TFA)-ACN]; B %: 10%-40%, 20 min). Give the compound 6 (0.800 g,1.14 mmol, 19.8% yield, TFA) as a yellow solid.

General Procedure for Preparation of Compound 7

To a solution of compound 6 (0.800 g, 1.14 mmol, 1 eq, TFA) in MeOH(10.0 mL) was added HCl/MeOH (4 M, 16.7 mL, 58.4 eq). The mixture wasstirred at 20° C. for 12 hrs. LCMS showed the reaction was complete. Themixture was concentrated in vacuum. The crude product was purified byreversed-phase HPLC (column: Phenomenex Luna C18 200*40 mm*10 um; mobilephase: [water (0.05% HCl)-ACN]; B %: 1%-20%, 10 min). Give the compound7 (0.500 g, crude, HCl) as a yellow solid.

General Procedure for Preparation of Compound 24

To a solution of compound 7 (0.150 g, 287.9 umol, 1 eq, HCl), TEA (291.3mg, 2.88 mmol, 400.7 uL, 10 eq) in DCM (5.00 mL) was added prop-2-enoylchloride (26.0 mg, 287.9 umol, 23.4 uL, 1 eq) in DCM (2.00 mL) dropwiseat −20° C. The mixture was stirred at −20° C. for 0.5 hr. LCMS showedthe reaction was complete. The mixture was concentrate in vacuum. Thecrude product was purified by reversed-phase HPLC (column: WelchUltimate AQ-C18 150*30 mm*5 um; mobile phase: [water (0.1% TFA)-ACN]; B%: 10%-40%, 12 min). Give the Compound 24 (38.0 mg, 58.1 umol, 20.1%yield, 99.8% purity, TFA) as a off-white solid.

¹H NMR: DMSO Varian_S_400 MHz

14.07 (br s, 1H), 13.43 (br s, 1H), 10.73 (s, 1H), 8.91 (br d, J=6.39Hz, 1H), 8.24 (br d, J=6.61 Hz, 1H), 8.13 (br d, J=8.38 Hz, 2H),7.71-7.83 (m, 3H), 7.20 (br d, J=6.61 Hz, 1H), 6.72 (s, 1H), 6.67 (br d,J=6.61 Hz, 1H), 6.09-6.27 (m, 2H), 5.68 (br d, J=11.03 Hz, 1H), 4.74 (brd, J=6.61 Hz, 1H), 4.51 (br d, J=7.50 Hz, 2H), 4.25 (br s, 4H), 4.11 (brs, 2H), 4.01 (s, 2H), 3.86 (br s, 4H)

General Procedure for Preparation of Compound 2a

To a solution of compound 1a (10.0 g, 58.1 mmol, 1 eq) in THE (200.0 mL)was added dropwise LDA (2 M, 69.7 mL, 2.4 eq) at −78° C. Then themixture was stirred at −78° C. for 15 min. After that dimethyl carbonate(5.24 g, 58.1 mmol, 4.89 mL, 1 eq) was added dropwise to the mixture.The reaction was warmed to 0° C. and stirred for 4 hrs. TLC (Petroleumether:Ethyl acetate=3:1, R_(f)=0.47) showed the reaction was complete.The reaction mixture was poured into a.q. NH₄Cl (200.0 mL) and extractedwith EtOAc (100.0 mL×3). The combined organic layers were washed withbrine (200.0 mL), dried over Na₂SO₄, filtered and concentrated underreduced pressure to give a residue. The crude for next step withoutpurification. Give the compound 2a (8.00 g, crude) as a red oil.

General Procedure for Preparation of Compound 3a

To a solution of compound 2a (6.00 g, 26.0 mmol, 1 eq) in DMF (60.0 mL)was added tert-butyl N-(azetidin-3-yl)carbamate (5.55 g, 26.6 mmol, 1.02eq, HCl) dicesium; carbonate (16.9 g, 52.1 mmol, 2 eq) and[2-(2-aminoethyl)phenyl]-chloro-palladium;dicyclohexyl-[2-(2,6-dimethoxyphenyl)phenyl]phosphane;2-methoxy-2-methyl-propane (991.9 mg, 1.30 mmol, 0.05 eq), the mixturewas stirred at 80° C. for 12 hrs. TLC (Dichloromethane:Methanol=10:1,R_(f)=0.28) showed the reaction was complete. The mixture was pouredinto H₂O (100.0 mL) and extracted with EtOAc (50.0 mL×3). Then theorganic phases were washed with brine (200.0 mL) dried over Na₂SO₄,filtered and concentrated under vacuum. The residue was purified bysilica gel chromatography eluted with Petroleum ether:Ethylacetate=100/1˜ 20/1˜ 10/1-1/1. Give the compound 3a (3.00 g, crude) as ayellow oil.

General Procedure for Preparation of Compound 1b

To a solution of compound 3a (2.00 g, 6.22 mmol, 1 eq) in MeOH (10.0 mL)was added NaOH (497.8 mg, 12.4 mmol, 2 eq) and H₂O (10.0 mL). Themixture was stirred at 20° C. for 3 hrs. TLC(Dichloromethane:Methanol=10:1, R_(f)=0) showed the reaction wascomplete. The reaction mixture was concentrated under reduced pressureto remove MeOH. The residue was diluted with H₂O (30.0 mL) and added 0.5M HCl to adjust pH=6. Then the mixture was extracted with DCM (20.0mL×3). The aqueous layer was concentrated under reduced pressure. Theresidue was diluted with MeOH (20.0 mL), filtered and concentrated underreduced pressure to give a residue. The crude for next step withoutpurification. Give the compound 1b (1.80 g, crude) as a yellow solid.

Example 16 Synthesis of Compound 25

General Procedure for Preparation of Compound 2

A solution of compound 1 (80.0 g, 520.9 mmol, 1 eq), Pd(dppf)Cl₂ (3.81g, 5.21 mmol, 0.01 eq) in THE (560.0 mL) was added dropwise MeMgBr (3 M,694.5 mL, 4.0 eq) at 25° C. under N₂. Then the mixture was stirred at60° C. for 16 hrs. TLC (Dichloromethane:Methanol=10:1, R_(f)=0.34)showed the reaction was completed. The reaction mixture was quenched byaddition NaHCO₃ (aq, 1.50 L), extracted with EtOAc (600.0 mL×4). Thecombined organic layers were washed with brine (600.0 mL), dried overNa₂SO₄, filtered and concentrated under reduced pressure to give aresidue. The crude product was triturated with MeCN (100.0 mL) at 25° C.for 2 hrs. Give the compound 2 (40.0 g, 300.4 mmol, 57.6% yield) as ayellow solid.

General Procedure for Preparation of Compound 3

To a solution of compound 2 (30.0 g, 225.3 mmol, 1 eq), t-BuONa (22.7 g,236.5 mmol, 1.05 eq) in THE (200.0 mL) was added dropwisebenzenesulfonyl chloride (43.3 g, 245.5 mmol, 31.4 mL, 1.09 eq) at 10°C., then the mixture was stirred at 25° C. for 1 hr. TLC(Dichloromethane:Methanol=10:1, R_(f)=0.54) showed the reaction wascompletely. The reaction mixture was added HCl (1M, 60.0 mL), thenextracted with EtOAc (300.0 mL×3). The combined organic layer was washedwith brine (200.0 mL), dried over Na₂SO₄, filtered and concentrated invacuum. The residue was purified by column chromatography (SiO₂,Petroleum ether:Ethyl acetate=100:1 to 0:1). Compound 3 (60.0 g, crude)was obtained as a yellow solid.

¹H NMR: DMSO Varian_S_400 MHz

8.82 (s, 1H), 8.16-8.10 (m, 2H), 8.00-7.94 (m, 1H), 7.78-7.72 (m, 1H),7.66 (d, J=8.2 Hz, 2H), 7.05 (d, J=4.0 Hz, 1H), 2.68-2.63 (m, 3H)

General Procedure for Preparation of Compound 4

A mixture of compound 3 (5.00 g, 18.2 mmol, 1 eq) in THE (35.0 mL) wasdegassed and purged with N₂ for 3 times, and was added, LDA (2 M, 11.8mL, 1.3 eq) and then the mixture was stirred at −78° C. for 1 hr underN₂ atmosphere, and then was added I₂ (6.04 g, 23.7 mmol, 4.79 mL, 1.3eq), the mixture was stirred at −78° C. for 1 hr under N₂ atmosphere.TLC (Dichloromethane:Methanol=10:1, R_(f)=0.66) showed the reaction wascompletely. The reaction mixture was partitioned between H₂O 100.0 mLand EtOAc 300.0 mL. The organic phase was separated, washed with brine150.0 mL (50.0 mL×3), dried over Na₂SO₄, filtered and concentrated underreduced pressure to give a residue. The crude product was used into thenext step without further purification. Compound 4 (9.00 g, crude) wasobtained as a brown solid.

General Procedure for Preparation of Compound 5

A mixture of compound 4 (9.00 g, 22.5 mmol, 1 eq), (4-aminophenyl)boronic acid (3.09 g, 17.8 mmol, 0.79 eq, HCl), K₂CO₃ (18.7 g, 135.2mmol, 6 eq), in dioxane (100.0 mL) and H₂O (10.0 mL) was degassed andpurged with N₂ for 3 times, then the mixture was stirred at 20° C. for0.5 hr, and then was added Pd(dppf)Cl₂ (1.65 g, 2.25 mmol, 0.1 eq) underN₂ atmosphere. The reaction was stirred at 100° C. for 10 hrs. TLC(Dichloromethane:Methanol=10:1, R_(f)=0.18) showed the reaction wascompletely. The reaction mixture was partitioned between EtOAc 500.0 mLand H₂O 200.0 mL. The organic phase was separated, washed with brine150.0 mL (50.0 mL×3), dried over Na₂SO₄, filtered and concentrated underreduced pressure to give a residue. The residue was purified by columnchromatography (SiO₂, Petroleum ether:Ethyl acetate=100:1 to 0:1).Compound 5 (2.50 g, 6.86 mmol, 30.4% yield) was obtained as a yellowsolid.

General Procedure for Preparation of Compound 6

To a solution of compound 5 (2.50 g, 6.86 mmol, 1 eq) in THE (15.0 mL)was added NaOH/MeOH (5 M, 9.60 mL, 7 eq). The mixture was stirred at 20°C. for 1 hr. LCMS showed the reaction was completely. The reactionmixture was partitioned between DCM 500.0 mL and H₂O 100.0 mL. Theorganic phase was separated, washed with brine 45.0 mL (15.0 mL×3),dried over Na₂SO₄, filtered and concentrated under reduced pressure togive a residue. Compound 6 (1.10 g, crude) was obtained as a yellowsolid.

General Procedure for Preparation of Compound 7

To a solution of compound 6 (600.0 mg, 2.68 mmol, 1 eq) in THE (5.00 mL)was added DMAP (163.4 mg, 1.34 mmol, 0.5 eq). After 30 mins,4-nitrophenyl carbonochloridate (539.2 mg, 2.68 mmol, 1 eq) was added tothe reaction. Then the reaction was stirred at 25° C. for 2 hrs. Thenthe compound 1d (353.59 mg, 1.34 mmol, 0.5 eq), K₂CO₃ (1.11 g, 8.03mmol, 3 eq) and TEA (1.35 g, 13.3 mmol, 1.86 mL, 5 eq) was added to thereaction. The reaction was stirred at 80° C. for 12 hrs. LCMS showed thereaction was completely. The reaction mixture was concentrated underreduced pressure to give a residue. The crude product was purified byreversed-phase HPLC (0.1% NH₃·H₂O or 0.1% FA condition). (column:Phenomenex luna C¹⁸ 250*50 mm*10 um; mobile phase: [water (0.1%TFA)-ACN]; B %: 10%-40%, 20 min). Compound 7 (0.400 g, 777.3 umol, 29.0%yield) was obtained as a off-white solid.

General Procedure for Preparation of Compound 8

To a solution of compound 7 (300.0 mg, 583.0 umol, 1 eq) in MeOH (5.00mL) was added HCl/MeOH (4 M, 145.7 uL, 1 eq). The mixture was stirred at20° C. for 12 hrs. TLC (Dichloromethane:Methanol=10:1) showed thereaction was completely. The reaction mixture was concentrated underreduced pressure to give a residue. Compound 8 (0.300 g, crude) wasobtained as a off-white solid.

General Procedure for Preparation of Compound 25

To a solution of 4-methylmorpholine (40.3 mg, 399.1 umol, 43.8 uL, 1.2eq) in THE (5.00 mL) was added acrylic acid (23.9 mg, 332.6 umol, 22.8uL, 1 eq) and isobutyl carbonochloridate (45.4 mg, 332.6 umol, 43.6 uL,1 eq) dropwise at −10° C., the mixture was filter and then was addedcompound 8 (0.150 g, 332.6 umol, 1 eq, HCl) and 4-methylmorpholine (67.2mg, 665.3 umol, 73.1 uL, 2 eq). The mixture was stirred at 15° C. for0.5 hr. LCMS showed the reaction was completely. The reaction mixturewas concentrated under reduced pressure to give a residue. The crudeproduct was purified by reversed-phase HPLC (0.1% NH₃·H₂O or 0.1% FAcondition) (column: Phenomenex Luna C¹⁸ 150*30 mm*5 um; mobile phase:[water (0.04% HCl)-ACN]; B %: 10%-37%, 10 min). Compound 25 (6.00 mg,12.8 umol, 3.85% yield, 89.9% purity) was obtained as a white solid.

¹H NMR: DMSO Varian_S_400 MHz

13.71 (br s, 1H), 11.21 (br s, 1H), 10.57 (s, 1H), 9.07-8.98 (m, 2H),8.04 (br d, J=8.8 Hz, 2H), 7.88 (br d, J=7.1 Hz, 1H), 7.66 (br d, J=8.8Hz, 2H), 7.52 (s, 1H), 6.45 (br d, J=5.1 Hz, 1H), 6.29-6.08 (m, 3H),5.67 (dd, J=2.1, 9.8 Hz, 1H), 4.73 (br d, J=6.6 Hz, 1H), 4.47 (br s,2H), 4.08 (br d, J=4.6 Hz, 2H), 2.92 (s, 3H)

General Procedure for Preparation of Compound 1c

A solution of compound 1a (10.0 g, 63.0 mmol, 1 eq), compound 1b (19.7g, 94.6 mmol, 1.5 eq, HCl) NaHCO₃ (13.2 g, 157.6 mmol, 6.13 mL, 2.5 eq)in DMSO (70.0 mL) was stirred at 80° C. for 12 hrs. TLC (Petroleumether/Ethyl acetate=0/1, R_(f)=0.24) showed the reaction was completed.The reaction mixture was poured into water (500.0 mL), extracted withEtOAc (300.0 mL×3). The combined organic layers were washed with brine(300.0 mL), dried over Na₂SO₄, concentrated in vacuum. The residue waspurified by column chromatography (SiO₂, Petroleum ether/Ethylacetate=50/1 to 1/1). Give compound 1c (13.0 g, 44.1 mmol, 70.0% yield)as a yellow solid.

General Procedure for Preparation of Compound 1d

To a solution of compound 1c (11.0 g, 37.3 mmol, 1 eq) in MeOH (110.0mL) was added Pd/C (5.00 g, 37.3 mmol, 10.0% purity, 1 eq) under N₂. Thesuspension was degassed under vacuum and purged with H₂ several times.The mixture was stirred under H₂ (50.0 psi) at 25° C. for 3 hrs. TLC(Petroleum ether/Ethyl acetate=0/1, R_(f)=0.07) showed the startingmaterial was consumed completely. The reaction mixture was filtered andthe filter was concentrated. The crude product was used for the nextstep without purification. Give the compound 1d (9.00 g, 34.0 mmol,91.1% yield) as a light yellow solid.

Example 17 Synthesis of Compound 26

General Procedure for Preparation of Compound 2

A solution of compound 1 (40.0 g, 230.4 mmol, 1 eq) and morpholine (42.1g, 483.9 mmol, 42.5 mL, 2.1 eq) in EtOH (400.0 mL) was stirred at 80° C.for 2 hrs. TLC (Petroleum ether:Ethyl acetate=3:1, R_(f)=0.44) showedthe reaction was complete. The reaction mixture was concentrated to givea residue. The residue was extracted with EtOAc (200.0 mL), filtered.The filter was concentrated in vacuum to give a residue. The residue wasused for the next step without purification. Give the compound 2 (51.0g, crude) as a yellow solid.

¹H NMR: CDCl₃ Bruker_F_400 MHz

7.77 (d, J=5.62 Hz, 1H), 6.07 (d, J=5.62 Hz, 1H), 5.98 (br s, 2H),3.74-3.80 (m, 4H) 3.39-3.45 (m, 4H)

General Procedure for Preparation of Compound 3

To a solution of SnCl₂·2H₂O (161.0 g, 713.6 mmol, 4 eq) in HCl (1.2 M,297.3 mL, 2 eq) was added compound 2 (40.0 g, 178.4 mmol, 1 eq) and EtOH(50.0 mL), the mixture was stirred at 80° C. for 12 hrs. TLC(Dichloromethane:Methanol=10:1, R_(f)=0.16) showed the reaction wascomplete. The reaction mixture was concentrated under reduced pressureto remove EtOH. The residue was diluted with H₂O (100.0 mL) and addeda.q. NaHCO₃ to adjust pH=10. Then the mixture was extracted with EtOAc(50.0 mL×7). The combined organic layers were washed with brine (200.0mL), dried over Na₂SO₄, filtered and concentrated under reduced pressureto give a residue. The crude for next step without purification. Givethe compound 3 (28.0 g, crude) as a red solid.

General Procedure for Preparation of Compound 4

To a solution of compound 3 (23.0 g, 118.4 mmol, 1 eq) in Tol. (200.0mL) was added MgSO₄ (14.2 g, 118.4 mmol, 1 eq) and 4-nitrobenzaldehyde(19.6 g, 130.2 mmol, 1.1 eq). The mixture was stirred at 115° C. for 12hrs. TLC (Dichloromethane:Methanol=10:1, R_(f)=0.65) showed the reactionwas complete. The solution was filtered and concentrated under reducedpressure to give a residue. The crude for next step withoutpurification. Give the compound 4 (35.0 g, crude) as a red oil.

General Procedure for Preparation of Compound 5

To a solution of SnCl₂·2H₂O (110.9 g, 491.8 mmol, 4 eq) in HCl (1.2 M,204.9 mL, 2 eq) was added compound 4 (40.0 g, 122.9 mmol, 1 eq) and EtOH(100.0 mL), the mixture was stirred at 80° C. for 12 hrs. TLC(Dichloromethane:Methanol=10:1, R_(f)=0.38) showed the reaction wascomplete. The reaction mixture was concentrated under reduced pressureto remove EtOH. The residue was diluted with H₂O (500.0 mL) and addeda.q. NaHCO₃ to adjust pH=7. Then the mixture was extracted with EtOAc(200.0 mL×3). The combined organic layers were washed with brine (500.0mL), dried over Na₂SO₄, filtered and concentrated under reduced pressureto give a residue. The residue was purified by silica gel chromatographyeluted with (Petroleum ether:Ethyl acetate=100/1˜ 20/1˜ 10/1-1/1). Givethe compound 5 (20.0 g, crude) as a yellow solid.

General Procedure for Preparation of Compound 6

To a solution of compound 5 (1.70 g, 5.76 mmol, 1 eq), compound 1b (1.77g, 5.76 mmol, 1 eq), TEA (4.08 g, 40.2 mmol, 5.61 mL, 7 eq) in DMF (10.0mL) was added HATU (3.28 g, 8.63 mmol, 1.5 eq). The mixture was stirredat 20° C. for 12 hrs. LCMS showed the reaction was complete. The mixturewas poured into H₂O (150.0 mL), then was filtered and filter cake wasconcentrated in vacuum. The crude product was purified by reversed-phaseHPLC (column: Phenomenex luna C18 250*50 mm*10 um; mobile phase: [water(0.1% TFA)-ACN]; B %: 10%-40%, 20 min). Give the compound 6 (0.800 g,1.14 mmol, 19.8% yield, TFA) as a yellow solid.

General Procedure for Preparation of Compound 7

To a solution of compound 6 (0.800 g, 1.14 mmol, 1 eq, TFA) in MeOH(10.0 mL) was added HCl/MeOH (4 M, 16.7 mL, 58.4 eq). The mixture wasstirred at 20° C. for 12 hrs. LCMS showed the reaction was complete. Themixture was concentrated in vacuum. The crude product was purified byreversed-phase HPLC (column: Phenomenex Luna C18 200*40 mm*10 um; mobilephase: [water (0.05% HCl)-ACN]; B %: 1%-20%, 10 min). Give the compound7 (0.500 g, crude, HCl) as a yellow solid.

General Procedure for Preparation of Compound 26

To a solution of compound 7 (0.200 g, 334.1 umol, 1 eq, TFA),(E)-4-(dimethylamino)but-2-enoic acid (55.3 mg, 334.1 umol, 1 eq, HCl),TEA (236.6 mg, 2.34 mmol, 325.5 uL, 7 eq) in DCM (5.00 mL) was addedHATU (190.5 mg, 501.1 umol, 1.5 eq). The mixture was stirred at 20° C.for 0.5 hr. LCMS showed the reaction was complete. The mixture wasconcentrate in vacuum. The crude product was purified by reversed-phaseHPLC (column: Phenomenex Luna C18 150*30 mm*5 um; mobile phase: [water(0.04% HCl)-ACN]; B %: 5%-30%, 10 min). Give the compound 8 (30.0 mg,46.6 umol, 13.9% yield, 98.3% purity, HCl) as a yellow solid.

¹H NMR: DMSO Bruker_E_400 MHz

14.71 (br s, 1H), 13.80 (br s, 1H), 13.48 (br s, 1H), 11.12 (br s, 2H),9.43 (br d, J=6.5 Hz, 1H), 8.13-8.26 (m, 3H), 7.81 (br d, J=8.7 Hz, 2H),7.72 (br d, J=6.8 Hz, 1H), 7.20 (d, J=6.8 Hz, 1H), 6.80 (s, 1H),6.68-6.77 (m, 1H), 6.64 (br d, J=6.7 Hz, 1H), 6.31 (br d, J=15.4 Hz,1H), 4.69-4.81 (m, 1H), 4.50 (q, J=9.2 Hz, 2H), 4.35 (br s, 4H), 4.15(br dd, J=9.8, 4.7 Hz, 2H), 4.09 (s, 2H), 3.85 (br s, 6H), 2.71 ppm (brd, J=4.4 Hz, 6H)

General Procedure for Preparation of Compound 2a

To a solution of compound 1a (10.0 g, 58.1 mmol, 1 eq) in THF (200.0 mL)was added dropwise LDA (2 M, 69.7 mL, 2.4 eq) at −78° C. Then themixture was stirred at −78° C. for 15 min. After that dimethyl carbonate(5.24 g, 58.1 mmol, 4.89 mL, 1 eq) was added dropwise to the mixture.The reaction was warmed to 0° C. and stirred for 4 hrs. TLC (Petroleumether:Ethyl acetate=3:1, R_(f)=0.47) showed the reaction was complete.The reaction mixture was poured into aq. NH₄Cl (200.0 mL) and extractedwith EtOAc (100.0 mL×3). The combined organic layers were washed withbrine (200.0 mL), dried over Na₂SO₄, filtered and concentrated underreduced pressure to give a residue. The crude for next step withoutpurification. Give the compound 2a (8.00 g, crude) as a red oil.

General Procedure for Preparation of Compound 3a

To a solution of compound 2a (6.00 g, 26.0 mmol, 1 eq) in DMF (60.0 mL)was added tert-butyl N-(azetidin-3-yl)carbamate (5.55 g, 26.6 mmol, 1.02eq, HCl) dicesium; carbonate (16.9 g, 52.1 mmol, 2 eq) and[2-(2-aminoethyl)phenyl]-chloro-palladium;dicyclohexyl-[2-(2,6-dimethoxyphenyl)phenyl]phosphane;2-methoxy-2-methyl-propane (991.9 mg, 1.30 mmol, 0.05 eq), the mixturewas stirred at 80° C. for 12 hrs. TLC (Dichloromethane:Methanol=10:1,R_(f)=0.28) showed the reaction was complete. The mixture was pouredinto H₂O (100.0 mL) and extracted with EtOAc (50.0 mL×3). Then theorganic phases were washed with brine (200.0 mL) dried over Na₂SO₄,filtered and concentrated under vacuum. The residue was purified bysilica gel chromatography eluted with Petroleum ether:Ethylacetate=100/1˜ 20/1˜ 10/1-1/1. Give the compound 3a (3.00 g, crude) as ayellow oil.

General Procedure for Preparation of Compound 1b

To a solution of compound 3a (2.00 g, 6.22 mmol, 1 eq) in MeOH (10.0 mL)was added NaOH (497.8 mg, 12.4 mmol, 2 eq) and H₂O (10.0 mL). Themixture was stirred at 20° C. for 3 hrs. TLC(Dichloromethane:Methanol=10:1, R_(f)=0) showed the reaction wascomplete. The reaction mixture was concentrated under reduced pressureto remove MeOH. The residue was diluted with H₂O (30.0 mL) and added 0.5M HCl to adjust pH=6. Then the mixture was extracted with DCM (20.0mL×3). The aqueous layer was concentrated under reduced pressure. Theresidue was diluted with MeOH (20.0 mL), filtered and concentrated underreduced pressure to give a residue. The crude for next step withoutpurification. Give the compound 1b (1.80 g, crude) as a yellow solid.

Example 18 Alternate Synthesis of Compound 10

General Procedure for Preparation of Compound 2

To a stirred solution of compound 1 (23.0 g, 137.5 mmol, 1 eq) in CHCl₃(200.0 mL) was added TEA (21.0 g, 207.7 mmol, 28.9 mL, 1.51 eq) andmethanesulfonyl chloride (17.8 g, 155.4 mmol, 12.0 mL, 1.13 eq) at 0° C.The mixture was stirred at 0° C. for 2 h. TLC(Dichloromethane:Methanol=10:1, R_(f)=0.62) showed the reaction wascomplete. The mixture was poured into ice H₂O (400.0 mL) and extractedwith DCM (200.0 mL×3). Then the organic phases were washed with brine(500.0 mL) dried over Na₂SO₄, filtered and concentrated under vacuum.The crude for next step without purification. Give the compound 2 (33.0g, crude) as a yellow solid.

¹H NMR: (400 MHz, CDCl₃)

δ 8.78 (d, J=5.1 Hz, 1H), 8.13 (s, 1H), 7.48-7.54 (m, 1H), 5.30 (s, 2H),4.00-4.04 (m, 3H), 3.10 ppm (s, 3H)

General Procedure for Preparation of Compound 4

To a solution of compound 2 (33.0 g, 134.5 mmol, 1 eq), compound 3 (53.9g, 269.1 mmol, 2 eq), K₂CO₃ (92.9 g, 672.7 mmol, 5 eq) in DMF (300.0 mL)was degassed and purged with N₂ for 3 times, and then the mixture wasstirred at 120° C. for 5 h under N₂ atmosphere. TLC(Dichloromethane:Methanol=10:1, R_(f)=0.55) showed the reaction wascomplete. The mixture was poured into H₂O (500.0 mL) and extracted withDCM (300.0 mL×3). Then the organic phases were washed with brine (1.00L) dried over Na₂SO₄, filtered and concentrated under vacuum. Theresidue was purified by silica gel chromatography eluted with Petroleumether:Ethyl acetate=100/1˜ 20/1˜ 10/1-1/1. Give the compound 4 (43.0 g,123.0 mmol, 91.4% yield) as a yellow solid.

General Procedure for Preparation of Compound 5

To a solution of compound 4 (43.0 g, 123.0 mmol, 1 eq) in THF (200.0 mL)was added LiOH·H₂O (15.4 g, 369.1 mmol, 3 eq) in H₂O (200.0 mL). Themixture was stirred at 20° C. for 3 h. TLC(Dichloromethane:Methanol=10:1, R_(f)=0) showed the reaction wascomplete. The mixture was poured into H₂O (100.0 mL) and extracted withDCM:MeOH=10:1 (100.0 mL×7). Then the organic phases dried over Na₂SO₄,filtered and concentrated under vacuum. The crude for next step withoutpurification. Give the compound 5 (33.0 g, crude) as a yellow solid.

¹H NMR: (400 MHz, DMSO)

δ 8.37 (d, J=4.9 Hz, 1H), 7.90 (s, 1H), 7.31-7.40 (m, 1H), 6.74 (br d,J=7.7 Hz, 1H), 3.46-3.61 (m, 2H), 3.40 (br s, 1H), 2.74 (br d, J=7.9 Hz,1H), 2.59 (br d, J=9.7 Hz, 1H), 1.76-1.91 (m, 2H), 1.70 (br d, J=9.0 Hz,1H), 1.55-1.65 (m, 1H), 1.42-1.50 (m, 1H), 1.35 (s, 9H), 1.04-1.19 ppm(m, 1H)

General Procedure for Preparation of Compound 6

To a solution of compound 5 (5.50 g, 18.6 mmol, 1 eq), compound 3A (9.99g, 29.8 mmol, 1.6 eq), DIEA (6.02 g, 46.5 mmol, 8.11 mL, 2.5 eq) in DCM(100.0 mL) was added T₃P (17.7 g, 27.9 mmol, 16.6 mL, 50% purity, 1.5eq). The mixture was stirred at 20° C. for 12 h. TLC(Dichloromethane:Methanol=10:1, R_(f)=0.51) showed the reaction wascomplete. The mixture was poured into H₂O (150.0 mL) and extracted withDCM (100.0 mL×3). Then the organic phases were washed with brine (500.0mL×3) dried over Na₂SO₄, filtered and concentrated under vacuum. Thecrude product was triturated with MeCN (150.0 mL) at 20° C. for 2 h.Give the compound 5 (4.00 g, crude) as a yellow solid.

General Procedure for Preparation of 7

To a solution of compound 5 (8.00 g, 13.0 mmol, 1 eq) in MeOH (50.0 mL)was added HCl/MeOH (4 M, 133.3 mL, 40.8 eq). The mixture was stirred at20° C. for 12 h. TLC (Dichloromethane:Methanol=10:1, R_(f)=0) showed thereaction was complete. The mixture was concentrated under vacuum. Thecrude product was purified by reversed-phase HPLC (column: Phenomenexluna C18 250*50 mm*15 um; mobile phase: [water (0.05% HCl)-ACN]; B %:1%-25%, 20 min). Give the Intermediate 7 (7.00 g, crude, HCl) as ayellow solid.

¹H NMR: (400 MHz, DMSO)

δ 13.07 (br s, 1H), 12.05 (br s, 1H), 10.88 (s, 1H), 8.86 (br d, J=4.4Hz, 1H), 8.41 (br s, 3H), 8.35 (s, 1H), 8.02-8.10 (m, 3H), 7.95-8.01 (m,2H), 7.42 (br s, 1H), 4.59 (br s, 2H), 4.00 (br d, J=4.4 Hz, 6H), 3.83(br d, J=4.2 Hz, 4H), 3.33-3.69 (m, 2H), 2.83-3.13 (m, 2H), 1.84-2.15(m, 3H), 1.53 (br s, 1H), 1.15-1.29 ppm (m, 1H)

General Procedure for Preparation of Compound 10

To a solution of Intermediate 7 (0.35 g, 637.4 umol, 1 eq, HCl) in DMF(6.00 mL) was added TEA (451.5 mg, 4.46 mmol, 621.0 uL, 7 eq) andprop-2-enoyl chloride (57.6 mg, 637.4 umol, 51.9 uL, 1 eq). Then themixture was stirred at 20° C. for 2 h. LCMS: showed the reaction wascomplete. Two batches were worked up together. The reaction mixture waspoured into H₂O (100.0 mL) and extracted with EtOAc (50.0 mL×5). Thenthe organic phases were washed with brine (100.0 mL) and concentratedunder vacuum. The crude product was purified by reversed-phase HPLC(column: Agela DuraShell C18 250*25 mm*10 um; mobile phase: [water (10mM NH₄HCO₃)-ACN]; B %: 35%-60%, 22 min). Give the Compound 10 (0.15 g,254.0 umol, 19.9% yield, 95.9% purity) as a yellow solid.

¹H NMR: (400 MHz, DMSO)

δ 12.20 (s, 1H), 10.74 (s, 1H), 8.68 (d, J=4.8 Hz, 1H), 8.18 (s, 1H),8.11 (s, 1H), 7.96-8.04 (m, 3H), 7.88-7.94 (m, 2H), 7.60-7.65 (m, 1H),7.16 (d, J=1.8 Hz, 1H), 6.17-6.28 (m, 1H), 6.01-6.09 (m, 1H), 5.53-5.58(m, 1H), 3.86-3.92 (m, 4H), 3.83 (br d, J=4.8 Hz, 1H), 3.72-3.79 (m,4H), 3.66 (s, 2H), 2.79 (br d, J=7.1 Hz, 1H), 2.65-2.69 (m, 1H), 2.04(br t, J=9.8 Hz, 1H), 1.90 (br t, J=9.7 Hz, 1H), 1.65-1.81 (m, 2H), 1.54(br d, J=11.0 Hz, 1H), 1.14-1.27 ppm (m, 1H)

General Procedure for Preparation of Compound 3

To a solution of compound 1 (50.0 g, 325.5 mmol, 1 eq), sodium;2-methylpropan-2-olate (32.8 g, 341.8 mmol, 1.05 eq) in THF (350.0 mL)was added dropwise compound 2 (62.6 g, 354.8 mmol, 45.4 mL, 1.09 eq) at10° C. The mixture was stirred at 25° C. for 2 h. TLC (Petroleumether/Ethyl acetate=1/1, R_(f)=0.59) showed the reaction was completed.The reaction mixture was added H₂O (100.0 mL), filtered and the filtercake was washed with MeOH (50.0 mL×3), concentrated in vacuum. Theresidue was used for the next step without purification. Give compound 3(80.0 g, 272.3 mmol, 83.6% yield) as a white solid.

¹H NMR: DMSO 400 MHz

8.79-8.85 (m, 1H), 8.11-8.20 (m, 3H), 7.74-7.81 (m, 1H), 7.64-7.72 (m,2H), 6.97 (d, J=4.0 Hz, 1H)

General Procedure for Preparation of Compound 4

To a solution of compound 3 (50.0 g, 170.2 mmol, 1 eq) in THE (300.0 mL)was added drop wise LDA (2 M, 127.6 mL, 1.5 eq) at −78° C. Then themixture was stirred at −78° C. for 1 h. Then I₂ (56.1 g, 221.2 mmol,44.5 mL, 1.3 eq) in THE (100.0 mL) was added to the mixture. The mixturewas stirred at −78° C. for 1 h. TLC (Petroleum ether/Ethyl acetate=1/1,R_(f)=0.71) showed the reaction was completed. HCl (1M, 200.0 mL) wasadded to the mixture. Then the mixture was concentrated in vacuum toremove THF. The residue was diluted with H₂O (100.0 mL), extracted withEtOAc (300.0 mL×3). The combined organic layers were washed with brine(500.0 mL), dried over Na₂SO₄, concentrated in vacuum. The crude productwas triturated with MeCN (200.0 mL) at 25° C. for 2 h. Give compound 4(50.0 g, 119.1 mmol, 70.0% yield) as a off-white solid.

¹H NMR: DMSO 400 MHz

8.75-8.79 (m, 1H), 8.08-8.14 (m, 2H), 7.75-7.82 (m, 1H), 7.65-7.73 (m,2H), 7.38 (s, 1H)

General Procedure for Preparation of Compound 1A

To a solution of compound 4 (70.0 g, 166.8 mmol, 1 eq) in THF (400.0 mL)was added NaOH/MeOH (5 M, 237.8 mL, 7.13 eq). Then the mixture wasstirred at 25° C. for 1 h. TLC (Petroleum ether/Ethyl acetate=0/1,R_(f)=0.62) showed the reaction was completed. The reaction mixture wasconcentrated under reduced pressure to remove THE and MeOH. The residuewas diluted with NH₄Cl (aq, 500.0 mL), filtered and the filter cake wasconcentrated under reduced pressure to give a residue. The crude productwas triturated with MeCN (50.0 mL) at 25° C. for 2 h. Give compound 1A(40.0 g, 143.1 mmol, 85.8% yield) as a brown solid.

¹H NMR: DMSO 400 MHz

13.14 (br s, 1H), 8.47-8.59 (m, 1H), 6.89 (s, 1H)

Additional Exemplary Compounds of the Invention

Other compounds of the invention have been or can be prepared accordingto the synthetic methods, or some variations thereof, described herein.The compounds can be prepared from readily available starting materialsusing the following general methods and procedures. It will beappreciated that where typical or preferred process conditions (i.e.,reaction temperatures, times, mole ratios of reactants, solvents,pressures, etc.) are given; other process conditions can also be usedunless otherwise stated. Optimum reaction conditions may vary with theparticular reactants or solvent used, but such conditions can bedetermined by one skilled in the art by routine optimization procedures.

The following compounds prepared or can be prepared from readilyavailable starting materials using the general methods and proceduresdescribed herein are depicted in Table 1:

TABLE 1 Representative compounds of the invention ID Structure MW  1

539.59  2

553.63  3

578.66  4

482.53  5

539.63  6

579.65  7

578.66  8

518.59  9

575.68 10

566.67 11

483.52 12

610.72 13

623.76 14

554.65 15

596.70 16

597.72 17

538.61 18

537.61 19

538.60 20

556.59 21

557.58 22

556.59 23

539.24 24

538.24 25

468.20 26

595.30

The following additional compounds can be prepared from readilyavailable starting materials using the general methods and proceduresdescribed herein are depicted below:

TABLE 2 Representative compounds of the invention ID Structure MW 101

580.69 102

637.79 103

553.67 104

584.66 105

641.75 106

557.67 107

580.69 108

637.79 109

553.67 110

591.68 111

580.69 112

507.20

The following additional compounds prepared or can be prepared fromreadily available starting materials using the general methods andprocedures described herein are depicted below:

Example 101a: Menin-MLL In Vitro Inhibitory Activity

The menin-MLL IC₅₀s of compounds disclosed herein is determined asdescribed below.

Cell Preparation:

The MLL-rearranged MOLM13 cell line and the MLL-germline cell line HL60growing in log phase cultures was counted and re-suspended at aconcentration of 10,000 cells/100 ul (100,000 cells/ml) in RPMI 10% FBScontaining medium with Pen/Strep.

A total of 100 uls were plated in each well of a round-bottom 96 wellnon-tissue treated plate (Corning). Thus, each well had 10,000 MOLM13 orHL60 cells on day.

Compound Dilution:

Each compound was diluted to a final concentration of 5 mM in DMSO. 15ml Falcon tubes were used for making the dilution. These 5 mM stockswere stored in 2 ml light-protective Eppendorf tubes in multiple 50 ulaliquots to prevent repeated freeze-thaw of the entire stock.

The following concentrations were decided for each compound: 0.01 uM,0.03 uM, 0.1 uM, 0.3 uM, 0.5 uM, 1 uM, 3 uM and 5 uM.

First, 2× working stocks for each desired concentration were made usingthe standard RPMI 10% FBS medium as the diluent.

Specifically, working stocks of 0.02 uM, 0.06 uM, 0.2 uM, 0.6 uM, 1 uM,2 uM, 6 uM and 10 uM (2× of the desired concentrations mentioned above)were made from the 5 mM stock (see note at the bottom for more details).

100 ul of each working stock dilution was added to the respective wellcontaining 100 ul of plated cells, thereby achieving a 1× drugconcentration. A similar strategy was used for the DMSO control arm.

Proliferation Assays:

Proliferation is measured using the BD Fortes' flow cytometry machineand FACS Diva software. Total numbers of live cells are measured bystaining cells with a dead cell stain such as Sytox. Cells arere-planted every 3-4 days and counting is performed on days 3, 7 and 10or 3, 6 and 9. Differentiation of cells is measured using CD11b as amarker of monocytic differentiation. Note: To minimize inaccuracies,once a stock of higher concentration was made, 10 fold dilutions weremade from that working stock. Eg: first the 10 uM 2× working stock wasmade by adding 4 ul of the 5 mM drug to 2 ml of medium. From this, the 1uM and 0.1 working stocks were made by vortexing the 10 uM stockvigorously and adding 90 ul of this to 810 ul of medium (1:10 dilution).Subsequently, a similar 1:10 dilution of the 1 uM stock (90 ul 1 uMstock+810 ul medium) gave a 0.1 uM working stock. In this way, 2×working stocks of 0.02 uM, 0.06 uM, 0.1 uM, 0.2 uM, 0.6 uM, 1 uM, 2 uMand 10 uM were made.

The IC₅₀s menin-MLL inhibition are determined using methods known to oneskilled in the art.

Example 101b: IC₅₀ Determination of Compounds of Invention in VariousCell Lines (Long Term Proliferation Assay) 1.1 Cell Lines

The following 5 cell lines are used or can be used for the long termproliferation assay (Table 2).

Cell Line Source Cat# Description MLL-rearrangement RS4; 11 ATCCCRL-1873 leukemia, acute lymphoblastic MLL-AF4 NOMO-1 JCRB IFO50474leukemia, acute monocytic MLL-AF9 leukemia HL-60 ATCC CCL-240 leukemia,acute promyelocytic MV-4-11 ATCC CRL-9591 leukemia, biphenotypic BMLL-AF4 myelomonocytic Molm-13 AddexBio C0003003 leukemia, acute,myeloid, leukemia MLL-AF9 suspension

TABLE 3A IC₅₀ Values for Exemplary Compounds of the Invention (CellTiter-Glo) Day 4 Day 7 Day 11 Day 14 Pat IC50 IC50 IC50 IC50 ID CellType (nM) (nM) (nM) (nM)  5 KG-1 >5000 >5000 4680 4070 MOLM-13 500 340350 360 OCI-AML-3 830 660 580 600 MV4-11 360 140 110 90 10 KG-1 470 330270 240 MOLM-13 100 50 50 80 OCI-AML-3 190 140 100 120 MV4-11 150 70 6050

TABLE 3B Additional IC₅₀ Values for Exemplary Compounds of the Invention(InCell) Pat Day 4 Day 11 ID Cell Type IC50 (nM) IC50 (nM)  5KG-1 >5000 >4470 MOLM-13 150 380 OCI-AML-3 450 460 MV4-11 420 490 10KG-1 520 300 MOLM-13 80 90 OCI-AML-3 110 120 MV4-11 170 170

TABLE 3C Comparison of Cell Titre Glo vs INCell at T4 and T11 forCompound 10 (first data set) and Compound 5 (second data set) Cell TypeTime point Read-out pIC50 IC50 (μM) % max pIC50 IC50 (μM) % max KG-1 T4CellTiter-Glo 6.33 0.47 99 <5.30 >5.00 <50 InCell *6.28 0.52 100<5.30 >5.00 <50 T11 CellTiter-Glo 6.57 0.27 99 5.33 4.68 59 InCell 6.520.30 100 5.35 4.47 52 MOLM-13 T4 CellTiter-Glo 7.01 0.10 98 6.30 0.50 98InCell 7.11 0.08 98 6.83 0.15 97 T11 CellTiter-Glo 7.32 0.05 99 6.450.35 99 InCell 7.04 0.09 98 6.42 0.38 98 MV4-11 T4 CellTiter-Glo 6.820.15 99 6.44 0.36 99 InCell 6.76 0.17 90 6.38 0.42 83 T11 CellTiter-Glo7.25 0.06 99 6.94 0.11 99 InCell 6.76 0.17 90 *6.31 0.49 83 OCI-AML3 T4CellTiter-Glo 6.72 0.19 99 6.08 0.83 97 InCell 6.96 0.11 100 6.35 0.45100 T11 CellTiter-Glo 7.00 0.10 99 6.24 0.58 99 InCell 6.91 0.12 1006.34 0.46 100Cells in Adhesion: pIC₅₀/IC₅₀ Summary table

TABLE 3D Cell in Adhesion pIC50/IC50 for Compound 10 (first data set)and Compound 5 (second data set) Cell Type Time point pIC₅₀ IC₅₀ (μM) %Max pIC₅₀ IC₅₀ (μM) % max SK-LU-1 T4 6.17 0.68 82 <5.30 >5.00 <50 T76.23 0.59 95 <5.30 >5.00 <50 T11 6.43 0.37 98 <5.30 >5.00 <50SK-LU-1/AMG510 T4 6.14 0.72 83 <5.30 >5.00 <50 T7 6.35 0.45 95<5.30 >5.00 <50 T11 6.41 0.39 98 <5.30 >5.00 <50 MIAPaCa-2 T4 6.57 0.2796 5.83 1.48 95 T7 6.64 0.23 98 6.06 0.87 98 T11 6.66 0.22 99 6.28 0.5299 MIAPaCa-2/AMG510 T4 6.53 0.30 92 6.09 0.81 92 T7 6.78 0.17 98 6.460.35 98 T11 6.82 0.15 99 6.57 0.27 99 NCI-H23 T4 6.45 0.35 92<5.30 >5.00 <50 T7 6.58 0.26 96 <5.30 >5.00 <50 T11 6.72 0.19 98<5.30 >5.00 <50 Panc 10.05 T4 6.10 0.79 84 <5.30 >5.00 <50 T7 6.31 0.4997 <5.30 >5.00 <50 T11 6.55 0.28 99 5.38 4.17 50

Long Term Proliferation Assay Design

Compounds of invention are tested in the 5 suspension lines by 14-daylong-term proliferation assay.

The compound is tested in 10-pt dose titration (client will determinethe starting concentration and the dilution scheme) and the final DMSOconcentration is kept at 0.2%.

Vehicle and media control are also included. All treatments are done intriplicate.

3 plates are used for each cell line and 15 plates are used for the 5cell lines.

Long Term Proliferation Assay Protocol

On Day 0, in a flat bottom 96-well plate, add 100 μL of cells per wellat the densities optimized. Prepare compounds in DMSO at 500× finalconcentration. Dilute the compounds with DMSO at the dilution. Dilutethe compounds in media at 3×final concentration. Add 50 μL of compoundor DMSO at 3× final concentration to each well. Final volume in eachwell is 150 μL, and final concentration of DMSO is 0.2%. Also include 3untreated control wells, by adding 50 μL of media alone. Incubate platesfor 96 hours.

Count the cells using the Acumen, with capabilities for 96-well plates.Pipette cells up and down to mix in each well, and add desired volume ofcells to a new flat bottom poly-D-lysine 96-well plate. Add Calcein AMat 1 μM final concentration. Let cells sit at RT for 10 mins followed bya quick spin to get cells settled on the bottom of the wells. Incubatethe plate for additional 40 mins in the incubator. Take out the plateand read by Acumen. Calculate the cell numbers taken into account thedilution factors.

Split the master plate. To do this take the total viable cell countcalculated using step:

-   -   1. Take the average of the replicates for each dose in order to        be used in splitting the cells.    -   2. Use a 96 well V-bottom plate to spin down the cells to remove        old media and compound to split the cells.    -   3. Based on the split ratio place the proper amount of media and        cells into the V-bottom plate, and spin the plate at 1100 rpm        for 5 minutes.    -   4. Following the spin remove the media, careful not to disturb        the cell pellet. Re-suspend pellet in 100 μL fresh media, and        add to a new 96-well flat bottom plate.    -   5. Add fresh compound, in the same manner as Step 3).    -   6. Incubate plates for 72 hours. Repeat steps 5)-10) on Day 7.    -   7. Incubate plates for 96 hours. Repeat Step 5)-10) on Day 11.    -   8. Incubate 72 hours and repeat step 5) to take a final count.    -   9. Data Analysis

To calculate growth for days 4, 7, 11, and 14:

-   -   1. Calculate the split factor for day 4 to 7, day 7 to 11, and        day 11-14. The split factor is the viable cells/mL on Day X        (either 4, 7 or 11) divided by the density the cells are being        split back to.    -   2. For growth of cells from day 4 to 7, multiply the day 7        viable cells/mL density by the split factor from day 4.    -   3. For growth of cells from day 7 to 11, multiply the day 11        viable cells/mL density by the days 4, and 7 split factors.    -   4. For growth of cells from Day 11 to 14, multiply the Day 14        viable cells/mL density by the days 4, 7, and 11 split factors.    -   5. Plot growth on semi-log chart (viable cells/mL on Y axis, in        log, and days on X axis).    -   6. The growth inhibition was calculated with the formula        ((untreated cell numbers−treated cell numbers)/untreated cell)).    -   7. Calculate the IC50 for each compound in each line using XLFit        (Sigmoidal Dose-Response Model,        y=(Bottom+((Top−Bottom)/(1+((IC50/x){circumflex over        ( )}Hill))))).

Example 102

The objective of the study was to evaluate the ability of compounds ofthe invention, inhibitors of Menin/MLL interaction to inhibit cellproliferation. The proliferation inhibitory effect was investigated intwo human MLL-leukemia cells selected on the bases of MLL fusion proteinand listed in Table 1. HL-60 cell line was used as negative control(Table 3).

Cell Type MLL gene fusion MV-4-11 MLL-AF4 MOLM-13 MLL-AF9

ATP is present in all metabolically active cells and is considered as amarker for cell viability and proliferation. The metabolic cell activitywas determined using the CellTiter-Glo kit from Promega, an ATPmonitoring system based on the production of luminescence by thereaction of ATP with added UltraGlo® recombinant luciferase (Kawano etal., 2016), according to the supplier's experimental recommendations.

Experimental Design

The described assay evaluates the ability of representative compounds ofinvention to inhibit the cell proliferation in the human MLL-leukemiacells plus a negative control cell line.

The assay provides potency values (IC₅₀) for each test compound at asingle time point Day 4 (T4).

Seven concentrations of the NCEs(2.00E-05-6.67E-06-2.22E-06-7.41E-07-2.47E-07-8.23E-08-2.74E-08M), wereassessed in duplicate in an individual test occasion in all the celllines. MI-503 (Borkin et al., 2015) was used as reference compound andwas tested at the same concentrations as the NCEs. 100% of proliferationis represented by the untreated cells (0.2% DMSO). The cell growth wasmonitored up to 4 days in culture.

Materials and Methods

Cell Culture

MV4-11, MOLM-13 and HL-60 cells (see Table 2) were maintained inRPMI-1640 medium (Invitrogen, Cat. n. 618700, Batch n. 1965930)supplemented with 10% of Heat Inactivated FBS (Invitrogen, Cat n. 10500,Batch n. 08Q8078K) and 1% Pen-Strep (Invitrogen, Cat. N. 15140, Batch n.1910859) and cultured at 37° C. in a humidified incubator with 5% CO2.All the cell lines grow in suspension and the cell density wasmaintained in a range of 2×10⁵-1×10⁶ viable cells/ml. Cells werepelleted at 130 g×5 min and conditioned medium was used to dilute thecell suspension.

TABLE 3 List of cell lines used in the study Cell density Cell lineSupplier/Vendor Cat. Number Batch Number (Cells/ml)* HL-60 ATCC/LCCCCL-240 63478792 15,000 MV4-11 ATCC/LCC CRL-9591 63567001 10,000 MOLM-13AddexBio/DBA C003003 126132 1,000 *Cell density at seeding (T0) TestItem Stock solution

TABLE 4 List of compounds tested Internal External Compound Compound IDID Batch ID MW MI-503 S781701 564.6 Compound 1 ET20241-115-P1 539.6

Test items were dissolved in glass vials at 10 mM in DMSO withpurity≥99.9% (Sigma, D8418, batch n. SHBH4245V) and stored at −20° C. in1.5 mL Eppendorf tubes.

Compound Plate Preparation

Serial dilutions 1 to 3 in DMSO 100% were prepared starting from a 10 mMstock solutions to generate 7 points concentration response curve (CRC).

For each plate to test, one 0.4 μL copy plate and four 0.3 μL copyplates were then stamped into 96-well plates not treated for celladhesion (Sarstedt—cat. no. 82.1581.001) by acoustic liquid Handling,Echo, at a concentration which was 500 fold the final assayconcentration. Stamped plates were stored at −20° C. The finalconcentrations for the reference compound, MI-503, and the test itemswere: 2.00E-05, 6.67E-06, 2.22E-06, 7.41E-07, 2.47E-07, 8.23E-08 and2.74E-08 M.

Long-Term Proliferation Assay Procedure

Cells were plated in 96-well flat bottom microtiter plates at celldensity of 15,000 cells/ml for HL-60, 1000 cells/ml for MOLM-13 and10,000 cell/ml for MV4-11. Cells were treated with 0.2% DMSO (Sigma,D8418, batch n. SHBH4245V) or serial dilutions of compounds (0.027 μM-20μM) in DMSO (0.2% final concentration). Cells were incubated in a 5% CO₂incubator at 37° C. for 4 days. A CellTiterGlo viability assay (Promega)was employed. Luminescence was read by using VictorV (Perkin Elmer)multilabel plate reader using the standard protocol for luminescence in96 well plate. The experiment was performed in duplicate.

Data Handling and Analysis

Data were expressed as % of inhibition compared to the 0.2% DMSOnegative control, and was calculated as follows:

% inhibition=100−[(RLU sample)×100/(RLU average controls*)]

-   -   cells containing 0.2% DMSO

CRCs were analysed by GraphPad and IC50 values were calculated bynon-linear regression using 4 parameter-logistic equation. IC50 (μM)values were reported in the final data table. The curve fittings wereperformed leaving free all the parameters. Any constrain were reportedin the results table.

Results

After visual inspection no solubility issues were observed for all thecompounds tested. Increasing concentrations of MI-503 inhibited cellviability in a concentration dependent manner in all the cell linestreated with IC₅₀ values of 0.42 μM in HL-60, 0.19 μM in MV4-11 and0.23p M in MOLM-13 (FIG. 1 , FIG. 2 and FIG. 3 ).

As shown in Table 5, Compound 1 inhibited the viability of MV4-11 andMOLM-13 with IC50 value of 0.15 μM and 0.20 μM. A similar effect wasobserved for both compounds in HL-60 cells with an IC50 of 0.19 μM forCompound 1.

TABLE 5 Inhibitory effect of Compound 1 and MI-503 on proliferation ofMOLM-13, MV4-11 and HL-60 cells. HL-60 MV4-11 (MLL-AF4) MOLM-13(MLL-AF9) IC50 % IC50 % IC50 % Compound μM pIC50 slope max μM pIC50slope max μM pIC50 slope max Compound 1 0.19 6.71 2.1 80 0.15 6.82 1.698 0.20 6.70 4.4 85 MI-503 0.42 6.38 1.0 103 0.19 6.73 1.4 100 0.23 6.631.0 98

CONCLUSIONS

MI-503 showed potency values in line with data previously obtained.

In MV4-11, MOLM-13 and HL-60 cells, Compound 1 showed similar potencyvalues; a similar profile was observed. Compound 1 displayed a steeperslope, reaching max inhibition at lower concentrations versus MI-503across all three cell lines.

Additional LTP Assay Data:

TABLE 7 Day 4 Day 7 Day 11 Day 14 Pat IC50 IC50 IC50 IC50 ID Cell Type(nM) (nM) (nM) (nM) 1 HL-60 790 600 780 890 MOLM-13 830 450 500 720(MLL-AF9) MV4-11 760 580 550 380 (MLL-AF4) RS4-11 550 112 >5 ND(MLL-AF4) 10 HL-60 430 260 290 270 MOLM-13 260 280 240 230 (MLL-AF9)MV4-11 460 290 220 200 (MLL-AF4) RS4-11 500 470 >5 ND (MLL-AF4)

TABLE 8 Day 4 Day 7 Day 11 Day 14 Pat IC50 IC50 IC50 IC50 ID Cell Type(nM) (nM) (nM) (nM) 13 HL-60 620 380 430 440 MOLM-13 420 350 80 190(MLL-AF9) MV4-11 600 510 320 280 (MLL-AF4) RS4-11 710 630 >5 ND(MLL-AF4) 15 HL-60 1150 680 850 890 MOLM-13 1020 410 320 330 (MLL-AF9)MV4-11 650 460 350 350 (MLL-AF4) RS4-11 1450 1550 >5 ND (MLL-AF4) 23HL-60 >5 >5 >5 >5 MOLM-13 >5 >5 1410 3890 (MLL-AF9) MV4-11 >5 4370 17001230 (MLL-AF4) RS4-11 1480 930 >5 ND (MLL-AF4)

Example 103—Alternate Long-Term Proliferation Assay Procedure

The day of the experiment (TO) all the cell line suspensions werecounted by Cell Viability Analyser, Vi-CELL and properly diluted withfresh medium to obtain the cell density reported in the Test Systemparagraph.

Cells were tested after 4 passages after thawing.

200 μL/well and 150p/well of cell suspension were added into the 0.4μL/well and 0.3 μL/well compound plates, respectively.

-   -   Cell plate containing 200 μL/well suspension was incubated at        37° C. in a humidified incubator with 5% CO₂.    -   From each well of the 150 μL/well cell assay plate, 100 μL were        harvested and transferred into a 96-well Optiplate (Perkin        Elmer, Cat. n. 6005290) and cell viability was measured as        described in 4.3 paragraphs (TO).    -   After four days in culture (T4) 150 μL/well of fresh medium were        added into a new 0.3 μL/well copy compound plate.    -   From each well of the 200 μL/well cell assay plate:    -   100 μL were sampled for the cell viability measurement as        described in 4.3 paragraphs (T4).    -   50 μL were harvested and added to the 150p/well compound plate        prepared as described in the first point to dilute 1:4 the cell        suspension.    -   The cell assay plate diluted and containing 200 μL/well        suspension were incubated at 37° C. in a humidified incubator        with 5% CO₂.

At T7-T11-T14 it was proceeded as described in T4, with the exceptionthat no further cell dilution was carried out at T14.

Cell Viability Measurement

Plates containing the samples to be tested were equilibrated at roomtemperature for approximately 30 min and then 30 μL/well of the PromegaCellTiterGlo® reagent were added. Contents will be mixed for 5 min on anorbital shaker to induce cell lysis and then incubated at roomtemperature for an additional 10 min to stabilize the luminescentsignal.

Luminescence was read by using VictorV (Perkin Elmer) multilabel platereader using the standard protocol for luminescence in 96 well plate.

Data Handling and Analysis

Data were expressed as % of inhibition compared to the 0.2% DMSOnegative control, and was calculated as follows:

% inhibition=100−[(RLU sample)×100/(RLU average controls*)]

-   -   *cells containing 0.2% DMSO

CRCs were analysed by GraphPad and IC₅₀ values were calculated bynon-linear regression using 4 parameter-logistic equation. IC₅₀ (μM)values were reported in the final data table.

The curve fittings were performed leaving free all the parameters. Anyconstrain were reported in the results table.

Results Cell Growth Curves

Cell growth curves were plotted as described in the experimental designsession and reported in Appendix 1.

MOLM-13 and MV4-11 cells grew exponentially along the 14 days in culturewith a growth rate cell type dependent.

HL-60 cells grew in an exponential manner up to 11 day in culture inboth the experiments. A growth slowdown was observed between T11 andT14.

RS4; 11 cells showed a slow growth profile up to 7 days in culturefollowed by a progressive decrease of growth with a significant signalreduction at T14. At T14 the cell viability was very low close to thelower detection limit with the absence of a workable signal window. Thedata obtained at this time point (T14) were excluded from the dataanalysis.

Cell Proliferation Inhibition

A visual inspection of treated wells was carried out along the entireperiod of the treatment to assess whether compound precipitationoccurred. No solubility issues were observed for any compound tested.

The effect of test substances to inhibit cell proliferation at differentend points is summarized in FIGS. 7 and 8 . pIC₅₀, IC₅₀, slope and %maximal effect at the highest tested concentration are reported.

Compound 10—At T4, increasing concentrations of Compound 10 fullyinhibited the cell viability of all the cells with similar potencyvalues. This compound profile was maintained along the 14 days inculture.Compound 13—At T4, increasing concentrations of Compound 13 fullyinhibited the cell viability of all the cells with similar potencyvalues. A leftward shift of the CRC with the increase of the time inculture was observed in MOLM-13 cells.Compound 15—At T4 Compound 15 fully inhibited the cell viability of allthe cell lines. A weak shift of potency was observed with the time inculture.

Compound 23-At T4 Compound 23 showed an effect only in RS4; 11. Alongthe 14 days in culture an increase of the effect was observed forMOLM-13 and MV4-11 cells while the absence of activity in HL-60 wasconfirmed up to T14.

Example 6: Pharmaceutical Compositions

The compositions described below are presented with a compound ofFormula (I)-(XLIIIc) for illustrative purposes.

Example 6a: Parenteral Composition

To prepare a parenteral pharmaceutical composition suitable foradministration by injection, 100 mg of a water-soluble salt of acompound of Formula (I)-(XLIIIc) is dissolved in DMSO and then mixedwith 10 mL of 0.9% sterile saline. The mixture is incorporated into adosage unit form suitable for administration by injection.

Example 6b: Oral Composition

To prepare a pharmaceutical composition for oral delivery, 100 mg of acompound of Formula (I)-(XLIIIc) is mixed with 750 mg of starch. Themixture is incorporated into an oral dosage unit for, such as a hardgelatin capsule, which is suitable for oral administration.

Example 6c: Sublingual (Hard Lozenge) Composition

To prepare a pharmaceutical composition for buccal delivery, such as ahard lozenge, mix 100 mg of a compound of Formula (I)-(XLIIIc) with 420mg of powdered sugar mixed, with 1.6 mL of light corn syrup, 2.4 mLdistilled water, and 0.42 mL mint extract. The mixture is gently blendedand poured into a mold to form a lozenge suitable for buccaladministration.

Example 6d: Inhalation Composition

To prepare a pharmaceutical composition for inhalation delivery, 20 mgof a compound of Formula (I)-(XLIIIc) is mixed with 50 mg of anhydrouscitric acid and 100 mL of 0.9% sodium chloride solution. The mixture isincorporated into an inhalation delivery unit, such as a nebulizer,which is suitable for inhalation administration.

Example 6e: Rectal Gel Composition

To prepare a pharmaceutical composition for rectal delivery, 100 mg of acompound of Formula (I)-(XLIIIc) is mixed with 2.5 g of methylcelluose(1500 mPa), 100 mg of methylparapen, 5 g of glycerin and 100 mL ofpurified water. The resulting gel mixture is then incorporated intorectal delivery units, such as syringes, which are suitable for rectaladministration.

Example 6f: Topical Gel Composition

To prepare a pharmaceutical topical gel composition, 100 mg of acompound of Formula (I)-(XLIIIc) is mixed with 1.75 g of hydroxypropylcelluose, 10 mL of propylene glycol, 10 mL of isopropyl myristate and100 mL of purified alcohol USP. The resulting gel mixture is thenincorporated into containers, such as tubes, which are suitable fortopical administration.

Example 6g: Ophthalmic Solution Composition

To prepare a pharmaceutical ophthalmic solution composition, 100 mg of acompound of Formula (I)-(XLIIIc) is mixed with 0.9 g of NaCl in 100 mLof purified water and filtered using a 0.2 micron filter. The resultingisotonic solution is then incorporated into ophthalmic delivery units,such as eye drop containers, which are suitable for ophthalmicadministration.

It is understood that the examples and embodiments described herein arefor illustrative purposes only and that various modifications or changesin light thereof will be suggested to persons skilled in the art and areto be included within the spirit and purview of this application andscope of the appended claims. All publications, patents, and patentapplications cited herein are hereby incorporated by reference in theirentirety for all purposes.

At least some of the chemical names of compounds of the invention asgiven and set forth in this application, may have been generated on anautomated basis by use of a commercially available chemical namingsoftware program, and have not been independently verified In theinstance where the indicated chemical name and the depicted structurediffer, the depicted structure will control. In the chemical structureswhere a chiral center exists in a structure but no specificstereochemistry is shown for the chiral center, both enantiomersassociated with the chiral structure are encompassed by the structure.

1.-126. (canceled)
 127. A compound selected from the group consistingof: 2-Pyridineacetic acid,4-[3-[[(1,1-dimethylethoxy)carbonyl]amino]-1-azetidinyl]-, methyl ester(1)

2-Pyridineacetic acid,4-[3-[[(1,1-dimethylethoxy)carbonyl]amino]-1-azetidinyl]- (2)

Urea, N-[4-(3-amino-1-azetidinyl)-2-pyridinyl]-N′[4-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl]- (3)

Carbamic acid,N-[1-[2-[[[[4-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl]amino]carbonyl]amino]-4-pyridinyl]-3-azetidinyl]-,1,1-dimethylethyl ester (4)

Benzenamine, 4-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)- (5)

Benzenamine,4-[4-methyl-7-(phenylsulfonyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]- (6)

7H-Pyrrolo[2,3-d]pyrimidine, 6-iodo-4-methyl-7-(phenylsulfonyl)- (7)

7H-Pyrrolo[2,3-d]pyrimidine, 4-methyl-7-(phenylsulfonyl)- (8)

2-Pyridineacetamide,4-(3-amino-1-azetidinyl)-N-[4-[4-(4-morpholinyl)-3H-imidazo[4,5-c]pyridin-2-yl]phenyl]-,hydrochloride (1:1) (1′)

Urea,N-[4-(3-amino-1-azetidinyl)-2-pyridinyl]-N′-[4-[4-(4-morpholinyl)-3H-imidazo[4,5-c]pyridin-2-yl]phenyl]-,hydrochloride (1.1) (2′)

Carbamic acid,N-[1-[2-[[[[4-[4-(4-morpholinyl)-3H-imidazo[4,5-c]pyridin-2-yl]phenyl]amino]carbonyl]amino]-4-pyridinyl]-3-azetidinyl]-,1,1-dimethyl ethyl ester (3′)

Benzenamine, 4-[4-(4-morpholinyl)-3H-imidazo[4,5-c]pyridin-2-yl]- (4′)

3H-Imidazo[4,5-c]pyridine, 4-(4-morpholinyl)-2-(4-nitrophenyl)- (5′)

2-Pyridineacetamide,4-(3-amino-1-azetidinyl)-N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-,hydrochloride (1:1) (6′)

Carbamic acid,N-[1-[2-[2-[[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]amino]-2-oxoethyl]-4-pyridinyl]-3-azetidinyl]-,1,1-dimethyl ethyl ester, hydrochloride (1:1) (7′)

Urea,N-(4-aminophenyl)-N′-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-(8′)

Urea,N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-N′-(4-nitrophenyl)-(9′)

2-Pyridinecarboxamide,4-[[(3R)-3-amino-1-piperidinyl]methyl]-N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-,hydrochloride (1.1) (10′)

Carbamic acid,N-[(3R)-1-[[2-[[[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]amino]carbonyl]-4-pyridinyl]methyl]-3-piperidinyl]-,11-dimethylethyl ester (11′)

2-Pyridinecarboxylic acid,4-[[(3R)-3-[[(1,1-dimethylethoxy)carbonyl]amino]-1-piperidinyl]methyl]-(9)

2-Pyridinecarboxylic acid,4-[[(3R)-3-[[(1,1-dimethylethoxy)carbonyl]amino]-1-piperidinyl]methyl]-,methyl ester (10)

Benzenemethanesulfonamide,4-amino-N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-(12′)

Benzenemethanesulfonamide,N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]- (13′)

Benzenemethanesulfonamide,4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]- (14′)

phenyl (R)-(4-(3-(but-2-ynamido)piperidin-1-yl)pyridin-2-yl)carbamate-(11)

2-Butynamide, N-[(3R)-1-(2-amino-4-pyridinyl)-3-piperidinyl]- (12)

N-[(3R)-1-(2-Nitro-4-pyridinyl)-3-piperidinyl]-2-butynamide (13)

3-Piperidinamine, 1-(2-nitro-4-pyridinyl)-, hydrochloride (1.1) (3R)-(14)

tert-butyl (R)-(1-(2-nitropyridin-4-yl)piperidin-3-yl)carbamate- (15)

Benzeneacetamide,4-amino-N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-(15′)

Benzeneacetamide,N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-nitro-(16′)

2-Pyridineacetic acid,4-[(3R)-3-[(1-oxo-2-butyn-1-yl)amino]-1-piperidinyl]- (16)

2-Pyridineacetic acid,4-[(3R)-3-[(1-oxo-2-butyn-1-yl)amino]-1-piperidinyl]-, ethyl ester (17)

2-Pyridineacetic acid, 4-[(3R)-3-amino-1-piperidinyl]-, ethyl ester (18)

2-Pyridineacetic acid,4-[(3R)-3-[[(1,1-dimethylethoxy)carbonyl]amino]-1-piperidinyl]-, ethylester (19)

Urea,N-[4-(3-amino-1-azetidinyl)-2-pyridinyl]-N′-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-,hydrochloride (1:1) (17′)

tert-butyl (1-(2-aminopyridin-4-yl)azetidin-3-yl)carbamate- (20)

tert-butyl (1-(2-nitropyridin-4-yl)azetidin-3-yl)carbamate- (21)

Benzenamine, 4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-(18′)

and 7H-Pyrrolo[2,3-d]pyrimidine, 6-iodo-4-(4-morpholinyl)- (19′)

or a salt thereof.
 128. The compound according to claim 127, wherein thecompound is selected from the group consisting of: 2-Pyridineaceticacid, 4-[3-[[(1,1-dimethylethoxy)carbonyl]amino]-1-azetidinyl]-, methylester (1)

2-Pyridineacetic acid,4-[3-[[(1,1-dimethylethoxy)carbonyl]amino]-1-azetidinyl]-(2)

Urea,N-[4-(3-amino-1-azetidinyl)-2-pyridinyl]-N′-[4-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl]-(3)

Carbamic acid,N-[1-[2-[[[[4-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl]amino]carbonyl]amino]-4-pyridinyl]-3-azetidinyl]-,1,1-dimethyl ethyl ester (4)

Benzenamine, 4-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)- (5)

Benzenamine,4-[4-methyl-7-(phenylsulfonyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]- (6)

7H-Pyrrolo[2,3-d]pyrimidine, 6-iodo-4-methyl-7-(phenylsulfonyl)- (7)

7H-Pyrrolo[2,3-d]pyrimidine, 4-methyl-7-(phenylsulfonyl)- (8)

2-Pyridinecarboxylic acid,4-[[(3R)-3-[[(1,1-dimethylethoxy)carbonyl]amino]-1-piperidinyl]methyl]-(9)

2-Pyridinecarboxylic acid,4-[[(3R)-3-[[(1,1-dimethylethoxy)carbonyl]amino]-1-piperidinyl]methyl]-,methyl ester (10)

phenyl (R)-(4-(3-(but-2-ynamido)piperidin-1-yl)pyridin-2-yl)carbamate-(11)

2-Butynamide, N-[(3R)-1-(2-amino-4-pyridinyl)-3-piperidinyl]- (12)

N-[(3R)-1-(2-Nitro-4-pyridinyl)-3-piperidinyl]-2-butynamide (13)

3-Piperidinamine, 1-(2-nitro-4-pyridinyl)- hydrochloride (11) (3R)- (14)

tert-butyl (R)-(1-(2-nitropyridin-4-yl)piperidin-3-yl)carbamate- (15)

2-Pyridineacetic acid,4-[(3R)-3-[(1-oxo-2-butyn-1-yl)amino]-1-piperidinyl]- (16)

2-Pyridineacetic acid,4-[(3R)-3-[(1-oxo-2-butyn-1-yl)amino]-1-piperidinyl]-, ethyl ester (17)

2-Pyridineacetic acid, 4-[(3R)-3-amino-1-piperidinyl]-, ethyl ester (18)

2-Pyridineacetic acid,4-[(3R)-3-[[(1,1-dimethylethoxy)carbonyl]amino]-1-piperidinyl]-, ethylester (19)

tert-butyl (1-(2-aminopyridin-4-yl)azetidin-3-yl)carbamate- (20)

and tert-butyl (1-(2-nitropyridin-4-yl)azetidin-3-yl)carbamate- (21)

or a salt thereof.
 129. The compound according to claim 127, wherein thecompound is selected from the group consisting of: 2-Pyridineacetamide,4-(3-amino-1-azetidinyl)-N-[4-[4-(4-morpholinyl)-3H-imidazo[4,5-c]pyridin-2-yl]phenyl]-,hydrochloride (1:1) (1′)

Urea,N-[4-(3-amino-1-azetidinyl)-2-pyridinyl]-N′-[4-[4-(4-morpholinyl)-3H-imidazo[4,5-c]pyridin-2-yl]phenyl]-,hydrochloride (1:1) (2′)

Carbamic acid,N-[1-[2-[[[[4-[4-(4-morpholinyl)-3H-imidazo[4,5-c]pyridin-2-yl]phenyl]amino]carbonyl]amino]-4-pyridinyl]-3-azetidinyl]-,1,1-dimethylethyl ester (3′)

Benzenamine, 4-[4-(4-morpholinyl)-3H-imidazo[4,5-c]pyridin-2-yl]- (4′)

3H-Imidazo[4,5-c]pyridine, 4-(4-morpholinyl)-2-(4-nitrophenyl)- (5′)

2-Pyridineacetamide,4-(3-amino-1-azetidinyl)-N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-,hydrochloride (1:1) (6′)

Carbamic acid,N-[1-[2-[2-[[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]amino]-2-oxoethyl]-4-pyridinyl]-3-azetidinyl]-,1,1-dimethylethyl ester, hydrochloride (1:1) (7′)

Urea,N-(4-aminophenyl)-N′-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-(8′)

Urea,N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-N′-(4-nitrophenyl)-(9′)

2-Pyridinecarboxamide,4-[[(3R)-3-amino-1-piperidinyl]methyl]-N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-,hydrochloride (1.1) (10′)

Carbamic acid,N-[(3R)-1-[[2-[[[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]amino]carbonyl]-4-pyridinyl]methyl]-3-piperidinyl]-,1,1-dimethylethyl ester (11′)

Benzenemethanesulfonamide,4-amino-N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-(12′)

Benzenemethanesulfonamide,N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-nitro-(13′)

Benzeneacetic acid,4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]- (14′

Benzeneacetamide,4-amino-N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-(15′)

Benzeneacetamide,N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-nitro-(16′)

Urea,N-[4-(3-amino-1-azetidinyl)-2-pyridinyl]-N′-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-,hydrochloride (1:1) (17′)

Benzenamine, 4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-(18′)

and 7H-Pyrrolo[2,3-d]pyrimidine, 6-iodo-4-(4-morpholinyl)- (19′)

or a salt thereof.
 130. The compound according to claim 127, wherein thecompound is 2-Pyridineacetic acid,4-[3-[[(1,1-dimethylethoxy)carbonyl]amino]-1-azetidinyl]-, methyl ester(1)

or 2-Pyridineacetic acid,4-[3-[[(1,1-dimethylethoxy)carbonyl]amino]-1-azetidinyl]- (2)

or a salt thereof.
 131. The compound according to claim 127, wherein thecompound is Benzenamine, 4-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-(5)

or a salt thereof.
 132. The compound according to claim 127, wherein thecompound is Carbamic acid,N-[1-[2-[[[[4-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenyl]amino]carbonyl]amino]-4-pyridinyl]-3-azetidinyl]-,1,1-dimethylethyl ester (4)

or a salt thereof.
 133. The compound according to claim 127, wherein thecompound is Benzenamine, 4-(4-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-(5)

Benzenamine,4-[4-methyl-7-(phenylsulfonyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]- (6)

7H-Pyrrolo[2,3-d]pyrimidine, 6-iodo-4-methyl-7-(phenylsulfonyl)- (7)

or 7H-Pyrrolo[2,3-d]pyrimidine, 4-methyl-7-(phenylsulfonyl)- (8)

or a salt thereof.
 134. The compound according to claim 127, wherein thecompound is 2-Pyridinecarboxylic acid,4-[[(3R)-3-[[(1,1-dimethylethoxy)carbonyl]amino]-1-piperidinyl]methyl]-(9)

or 2-Pyridinecarboxylic acid,4-[[(3R)-3-[[(1,1-dimethylethoxy)carbonyl]amino]-1-piperidinyl]methyl]-,methyl ester (10)

or a salt thereof.
 135. The compound according to claim 127, wherein thecompound is phenyl(R)-(4-(3-(but-2-ynamido)piperidin-1-yl)pyridin-2-yl)carbamate- (11)

2-Butynamide, N-[(3R)-1-(2-amino-4-pyridinyl)-3-piperidinyl]- (12)

N-[(3R)-1-(2-Nitro-4-pyridinyl)-3-piperidinyl]-2-butynamide (13)

2-Pyridineacetic acid,4-[(3R)-3-[(1-oxo-2-butyn-1-yl)amino]-1-piperidinyl]- (16)

or 2-Pyridineacetic acid,4-[(3R)-3-[(1-oxo-2-butyn-1-yl)amino]-1-piperidinyl]-, ethyl ester (17)

or a salt thereof.
 136. The compound according to claim 127, wherein thecompound is 3-Piperidinamine, 1-(2-nitro-4-pyridinyl)-, hydrochloride(1:1), (3R)- (14)

or tert-butyl (R)-(1-(2-nitropyridin-4-yl)piperidin-3-yl)carbamate- (15)

or a salt thereof.
 137. The compound according to claim 127, wherein thecompound is 2-Pyridineacetic acid, 4-[(3R)-3-amino-1-piperidinyl]-,ethyl ester (18)

or 2-Pyridineacetic acid,4-[(3R)-3-[[(1,1-dimethylethoxy)carbonyl]amino]-1-piperidinyl]-, ethylester (19)

or a salt thereof.
 138. The compound according to claim 127, wherein thecompound is tert-butyl (1-(2-aminopyridin-4-yl)azetidin-3-yl)carbamate-(20)

or tert-butyl (1-(2-nitropyridin-4-yl)azetidin-3-yl)carbamate- (21)

or a salt thereof.
 139. The compound according to claim 127, wherein thecompound is 2-Pyridineacetamide,4-(3-amino-1-azetidinyl)-N-[4-[4-(4-morpholinyl)-3H-imidazo[4,5-c]pyridin-2-yl]phenyl]-,hydrochloride (1.1) (1′)

Urea,N-[4-(3-amino-1-azetidinyl)-2-pyridinyl]-N′-[4-[4-(4-morpholinyl)-3H-imidazo[4,5-c]pyridin-2-yl]phenyl]-,hydrochloride (1:1) (2′)

Carbamic acid,N-[1-[2-[[[[4-[4-(4-morpholinyl)-3H-imidazo[4,5-c]pyridin-2-yl]phenyl]amino]carbonyl]amino]-4-pyridinyl]-3-azetidinyl]-,1,1-dimethyl ethyl ester (3′)

2-Pyridineacetamide,4-(3-amino-1-azetidinyl)-N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-,hydrochloride (1.1) (6′)

Carbamic acid,N-[1-[2-[2-[[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]amino]-2-oxoethyl]-4-pyridinyl]-3-azetidinyl]-,1,1-dimethylethyl ester, hydrochloride (1:1) (7′)

or Urea,N-[4-(3-amino-1-azetidinyl)-2-pyridinyl]-N′-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-,hydrochloride (1:1) (17′)

or a salt thereof.
 140. The compound according to claim 127, wherein thecompound is Urea,N-(4-aminophenyl)-N′-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-(8′)

Urea,N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-N′-(4-nitrophenyl)-(9′)

Benzeneacetamide,4-amino-N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-(15′)

or Benzeneacetamide,N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-nitro-(16′)

or a salt thereof.
 141. The compound according to claim 127, wherein thecompound is Benzenamine,4-[4-(4-morpholinyl)-3H-imidazo[4,5-c]pyridin-2-yl]- (4′)

or 3H-Imidazo[4,5-c]pyridine, 4-(4-morpholinyl)-2-(4-nitrophenyl)- (5′)

or a salt thereof.
 142. The compound according to claim 127, wherein thecompound is 2-Pyridinecarboxamide,4-[[(3R)-3-amino-1-piperidinyl]methyl]-N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-,hydrochloride (1:1) (10′)

or Carbamic acid,N-[(3R)-1-[[2-[[[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]amino]carbonyl]-4-pyridinyl]methyl]-3-piperidinyl]-,1,1-dimethylethyl ester (11′)

or a salt thereof.
 143. The compound according to claim 127, wherein thecompound is Benzenemethanesulfonamide,4-amino-N-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-(12′)

or BenzenemethanesulfonamideN-[4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenyl]-4-nitro-(13′)

or a salt thereof.
 144. The compound according to claim 127, wherein thecompound is Benzeneacetic acid,4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]- (14′)

or a salt thereof.
 145. The compound according to claim 127, wherein thecompound is Benzenamine,4-[4-(4-morpholinyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]- (18′)

or a salt thereof.
 146. The compound according to claim 127, wherein thecompound is 7H-Pyrrolo[2,3-d]pyrimidine, 6-iodo-4-(4-morpholinyl)- (19′)

or a salt thereof.